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by: Clarissa Hermiston DVM


Clarissa Hermiston DVM

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This 58 page Class Notes was uploaded by Clarissa Hermiston DVM on Monday October 5, 2015. The Class Notes belongs to BIO 127 at California State University - Sacramento taught by Staff in Fall. Since its upload, it has received 9 views. For similar materials see /class/218818/bio-127-california-state-university-sacramento in Biological Sciences at California State University - Sacramento.

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Date Created: 10/05/15
B10 127 Vertebrate Embryology Fall 2004 Lecture Outline for Section 2 In the following sections we will begin our study ofEmbryology in earnest We will rst investigate the mechanisms by which cells differentiate into new phenotypes We will then use these ideas to study the early stages of development those that give us the basic organization ofthe embryo This organization includes the differentiation of cells into the three layers of the gastrula the formation of directional axes in the embryo what will be front and rear what will be top and bottom left to right and we will then move onto the development ofthe ectodermal layer Cell fates and embryo organization through these developmental points are amazingly similar across a wide variety ofspecies The ectoderm will give rise to the nervous system however so vertebrates will have some obvious differences here A wise man once told me The most important event to occur in your entire life was gastrulation Consider yourselves wonders of nature baby it is truly amazing that any of us have got this far VII Early Development Early development the period of development that ends with gastrulation is the critical period that determines the fate of most conceived embryos A remarkably high percentage of fertilized eggs in mammals particularly those of humans do not produce Viable offspring The main reason for this is that extended development of malformed embryos is too taxing an energy demand on the mother In most cases these embryos are reabsorbed and their components reused as soon as the fatal aw is detected Some aws escape detection due to their late onset or their low impact in the developing embryo and because the mother provides much of the essential metabolism of the early embryo Thus inborn errors of metabolism are the most prevalent genetic disorders found in infants It is easy to theorize Why the reliance on large numbers of offspring for species survival tends toward simpler organisms 7 not those as complicated as ourselves A Cell Fates Differentiation Commitment Specification and Determination During embryonic development cells must divide to enlarge the embryo and must differentiate to become the many types of cells possessed by the adult organism Under most conditions the two events are linked 7 the daughter cells are not the same as the parent cell So how does one daughter cell choose one fate over another Let s nd out 1 Differentiation Cell Fate and Other Key Ideas a Differentiation is the expression of a different phenotype in the daughter cells than that expressed in the parent cell The embryo starts with few cells becomes many and these later cells have very different functions Because of this differentiation must be organized and progressive eg each step must restrict the options that the daughter cells have or you might have all of your cells make arms but no legs ectoderm but no mesoderm Ex trophoblasts 1 Cell fate is the type of cell that a differentiating cell chooses or is directed to have the potential become It can also refer to a multistep pathway required to reach that cell type for non embryonic fates only 2 Potential or competence refers to a cell s ability to reach a given fate This re ects its past history and its position in the embryo 3 Commitment to a fate path is the nal restriction ofa cell s choices a Speci cation is a reversible stage of commitment that will continue even if taken out of the embryo and put in a neutral environment b Determination is an irreversible ability to complete differentiation even when placed in a nonneutral area of the embryo b The Big Idea of cell differentiation is that a given cell s fate choices are determined by its current position in the embryo the soluble and insoluble environments around it and the history of its predecessors that got it to that point 1 Receptor Summation Morphogens and Morphogenetic Fields p 63 a Think of all cells as existing Within the neuronal model you ve already learned 7 summation of inputs b Cell fate is largely determined by immediate neighbors and matrix molecules c Soluble morphogen gradients add to the summed signals a cell receives d Cells in a given region tend to commit to related fates 2 Mechanisms of Cell Speci cation a Autonomous Speci cation p 56 1 Mostly invertebrate embryos 2 Cells of the earliest divisions have restricted fates based on egg cytosol 3 A cell killed at the 4 or 8cell stage will cost the embryo all of its descendents b Conditional Speci cation p 58 1 Most vertebrate embryo cells Invertebrates also use it 2 Cells have restricted fates based on environmental restrictions 3 A change in environment will produce a change in fate 4 Advantage is that if a cell is lost others can take its place B Mechanisms 0fDi erential Gene Expression The study of Developmental Biology is all about the Dominance of Phenotype The genotype may determine the choice of traits that an organism or cell has but it is the expression of those traits that dominates this eld Phenotype is the result of protein activity exclusively So how do we get so many different kinds of cells each with its different complement of gene products expressed This section looks at the control of phenotypic expression in the nucleus eg mRNA expression and processing and in the cytosol mRNA translation and protein modi cation 1 Control of Gene Expression in the Nucleus p 107 a DNA Anatomy Governs Access by Transcription Machinery Expressibility l Chromatin Structure 7 Half DNA Half Protein by Weight a Heterochromatin vs Euchromatin b The defaultstate is inaccessible 2 Gene Structure Exons and Introns a You already know the basics here 7 sequences that exit the nucleus exons vs those that remain inside introns 3 Gene Structure Untranslated Regions UTRs Promoters and Enhancers Transcription and Translation StartSites TATAboxes and Termination Sequences a DNA sequences found in 3 UTR that do not themselves get expressed but dictate when and where that gene gets expressed b 5 and 3 UTRs have lots ofinformation in them b Transcription Factors Determine Speci city l Basal Transcription Factors set the transcription machine RNA Polymerase a It takes at least six proteins to get RNA polymerase to bind to DNA b Transcription Factor IID binds the TATAbox 2 TissueSpeci c Transcription Factors are the real source of differentiation 3 Transcription Factor Cascades a Increasing expression of tissuespeci c factors driven by those expressed previously leads to a lockdown of phenotype b Cardiac muscle example c Methylation and Acetylation and Control of Transcription p 121 l Promoter Methylation Gives Stable Gene Inactivation a 5methylcytosine in Vertebrates b Is This Why We Can t Grow New Limbs 2 Chromatin Methylation Gives Stable Cell Differentiation a The MethylationAcetylation Switch b Protein Interactions with Methylated DNA c Methylation and Cloning 3 Compensation for X Chromosome Dosage in Males and Females a Male Flies Acetylate Their One X Chromosome b Female Mammals Methylate Their Second X Chromosome c Reactivation in Germ Cells Prior to Meiosis d RNA Processing in the Nucleus l The Basic Steps a Primary RNA transcripts are made into mRNA by removal of their introns in the nucleus b mRNA transcripts are then transported from the nucleus to the ribosomal complexes in the cytosol through the nuclear pore 2 Nuclear RNA Selection a More primary transcripts are made than are allowed to become mRNA b In one case the exons go to the cytosol to be degraded while the introns assist in nucleolus construction 3 Differential mRNA Splicing a Different cells make different proteins out of the same transcript by splicing in different exons sometimes introns b Splice sites in the 5 and 3 end of introns can be recognized differently in different cells c Splicing isoforms are protein families made from one gene and can even occur in the same cell at the same time d One Drosophila gene has theoretical ability to produce 38016 proteins 7 more than three times the total number of y genes 2 Control of Expression in the Cytosol a RNA Processing in the Cytosol 1 Differential mRNA Longevity a The length of the polyA tail determines longevity b Different transcript isoforms have different longevity 2 Selective inhibition of mRNA Translation a Stored maternal RNAs are found in the egg cytosol b 5 caps and polyA tails c Amphibian maskin makes inactive plasmids d Protein inhibitors 7 smaug and nanos in Drosophila e Antisense RNAs 7 small regulatory RNAs 1 RNA regulation is an important emerging area of research 3 Differential mRNA Localization a This is also a critical phenomenon in oocytes b RNAs are stored in different regions of the egg and end up in different daughter cells because of it b Protein Processing in the Cytosol l PostTranslational Modi cation a Traf cking sequences that direct destination b The preproprotein phenomenon c Subunit assembly d Cofactors e Acectylation methylation phosphorylation etc C Gastrulation Gastrulation is the highly ordered and integrated movement of the cells of the blastula to form the three primordial layers the endoderm mesoderm and ectoderm This is one of the most amazing events in embryology Nearly all organisms undergo the same basic processes although they look very different due to the yolkdetermined shape of the blastula The formation of the blastula established the starting positions of a great number of cells 7 gastrulation changes everything 1 Formation ofthe primordial layers a The blastula either inner cell mass or epiblast carries all the potential cell fates b The endodermal progenitor cells must nd their way deep into the center of embryo c The mesodermal cells must migrate less far and form an intermediate sheet d The cells that don t migrate through the blastopore remain to form ectoderm 2 A few key concepts and terms a Epithelial in the embryo denotes a sheet of any kind b Epiboly is the word for migration of a sheet of epithelial cells c Mesenchymal denotes individually migrating cells d Delamination is what epithelial cells do when they become mesenchymal cells 3 Gastrulation in the Yolk Rich Chick Embryo p 356 a Starts from the twolayered blastula epiblast and hypoblast with blastocoel between 1 Remember the epiblast carries all embryonic cell fates b Formation of the primitive streak l Arises as a lump in the posterior marginal zone of the epiblast 2 Cells become migratory and digest the matrix beneath them 3 Close in tight and begin to migrate anteriorly 7 appear to be one population 4 The front remains thickened and is called Hensen s node 5 The migration is coordinated with the eXtension of the secondary hypoblast 6 Streak eXtends to 75 of area pellucida c The primitive groove 1 Anterior migration leaves a digested depression in its wake 2 Allows epiblast cells to migrate through into blastocoel d The initial migration through the groove 1 Mesenchymal migration through the groove then moves anterior 2 Form the endodermal and mesodermal structures of the head and neck 3 Presumptive endoderm displaces the hypoblast as it moves e The second wave of migration forms two deep layers throughout the embryo l Mesenchymal cells continue to pour over the lip of the groove 2 The deepest migrators become endoderm 7 nished in about 1418 hours 3 Many times their number form the mesodermal layer and takes much longer f Regression of the node leaves the notochord l The node then regresses back toward posterior 2 At this point all cells left on surface have ectodermal fates 3 Notochord forms in the poterior direction in wake of regressing node 4 All development of the embryo is head to tail due to this pattern g Epiboly of the ectoderm surrounds the entire yolk l Herculean task 7 takes four days 4 A Couple of Alternative Designs a Amphibians are yolkintermediate and more spherical 1 Use a blastopore rather than a primitive streak 2 Most migrations are epiboly b Mammals are yolkpoor and spherical 1 Follow the exact pattern of the discoidal chick D Axis Speci cation There are three principle axes in the body anteriorposterior dorsalventral and rightleft How do the cells of the embryo know where to go to become head vs tail How does the heart know to form on the left side of the body A lot of inquiring minds want to know and slowly we are guring it all out 1 Axis Formation in the Chick p 360 a Speci cation occurs during cleavage formation occurs during gastrulation b DorsalVentral AXis Determination l Primarily pH determined a pH of albumin above epiblast is high 95 b pH of blastocoel below epiblast is low 65 2 Gives a transmembrane potential of 25mV 3 The aXis can be reversed eXperimentally by pH or voltage changes c AnteriorPosterior l Primarily gravity determined a Egg is rotated in shell gland for 20 hours at 1012 revolutions per hour b Lighter yolk parts accumulate tip up that end make it posterior 2 Hypothesis is that this gives a starting point for 2 hypoblast growth a Displacement of l0 hypoblast changes growth factors made 3 Formation of the organizer a It is known that this is where the organizer will form 1 All of the marginal zone is capable but only posterior is site b Cells in the posterior marginal zone start to eXpress VGl and nodal 1 Forms an active group of cells called the Nieuwkoop Center c The Nieuwkoop Center signals other cells to form Hensen s Node 1 This starts the primitive streak d Henson s Node then becomes the mobile organizer 1 First it eXpresses FGFS which preps ectoderm to be neural 2 Then expresses sonic hedgehog chordin noggin and nodal 3 Organizes gastrulation on the way out 4 Organizes notochord formation on the way back c LeftRight Axis Formation 1 Growth factor and transcription factor determined 2 At maximum extension of primitive streak a Activin expression begins on right side of embryo 1 No doubt something Henson s Node did 2 Stops sonic hedgehog expression on that side only 3 Stimulates FGFS expression on that side only b Downstream of a complex cascade two transcription factors differ l snail is expressed on the right side 2 PitxZ is expressed on the leftside 3 Experimentally reversing any step in the cascade randomizes leftright axis a The heart and spleen have a 5050 chance of being on the right side b The liver has a 5050 chance ofbeing on the left side 2 Axis Formation in Mammals p 375 a The dorsalventral and leftright axis are still kind of a black box 1 Axis appears related to contact with trophoblasts vs blastocoel 2 Leftright appears related to differential transcription factor expression a Perhaps similar to chick 7 situs inversus gene b Anteriorposterior patterning 1 There appear to be two organizers a One at each end producing double gradients of secreted molecules 2 Ultimately leads to hox gene expression and regional patterning VIII Development Of the Ectoderm In the last section we talked about the formation of the epiblast and then the migration of huge numbers of cells through the primitive streak to adopt endodermal and mesodermal fates In addition the regression of Henson s Node left behind the notochord in the mesoderm But what of those that don t migrate into the blastocoel Are they left to pine for a greater fate of travel and adventure In fact those cells that remain at the dorsal surface make up the ectodermal layer or plate and life has great things in store for most of them Neurons From the simple leftovers of the epiblast to the source of thought emotion and systemic control of the entire organism We ll also look at the fates of other cells from the ectoderm as they become components of the skin and yet others those of the neural crest that become an amazing diversity of cells This is a good time to be last 7 your descendents shall rule their world A Neurulation By de nition the formation of the neural tube from the cells of the epiblast The neural tube then gives rise to the central nervous system the brain and spinal cord Obviously restricted to the family Chordata the process involves formation of the neural tube its differentiation along its length and the differentiation of central nervous system neurons Some very sophisticated neuronal tissues have developed over the millennia and we will look at the example of the vertebrate eye 1 The Signals Which Differentiate Neural Cells p 391 a A Quick Review of a Few Good Words 1 Speci cation Determination Competence Terminal Differentiation b A Few Good Guesses l Competence is established by broblast growth factors FGFs 2 Speci cation is due to chordin noggin and follistatin 3 Determination is accomplished by insulinlike growth factors IGFs 4 Lateral regions of the epiblast are nonneuronal a These cells make Wnts and FGFs are inhibited by Wnts 2 Formation ofthe Neural Tube p 393 a Terminology 1 Primary Neurulation 7 the anterior portion of the neural plate invaginates and curls up to form a tube 2 Secondary Neurulation 7 the posterior portion coalesces as a solid cord from surrounding mesenchymal cells and then hollows out into a tube b Formation of the Neural Plate and the Presumptive Epidermis l Signals to ectoderm cells come from mesoderm and endoderm below 2 The cells at the center of the ectoderm become columnar and neural 3 As the embryo elongates so does the neural plate and epidermis c Formation of the Neural Folds and the Neural Groove l Folds result from the formation of two hinge regions a Medial Hinge Point forms along notochord b Dorsolateral Hinge Points form along neuroepidermal border 2 Hinging is cytoskeletal change in neural cells and epidermal eXpansion a Cell wedging is due to microtubules forcing increased height and micro laments pinching in the apical ends of the cells b Inward folding is forced by growth of epidermal cells d Closure of the Neural Tube 1 As the two folds contact they adhere and merge a Around this time the neural crest cells migrate away 2 This process occurs generally anterior to posterior a Tube is closing up front before gastrulation is nished in back 3 Regions close at different times and at different rates 7 l in 500 fail a Spina bi da is a failure of the posterior neural tube to close b Anencephaly is a failure of the anterior tube to close c Craniorachischisis is complete failure to close d Folic acid and uneXplained seasonal effects are related e Secondary Neurulation in the Posterior of the Embryo l Individually migrating mesenchymal cells condense a Even before Hensen s Node forms a notochord in the region 2 Form a solid cord underneath the surface ectoderm 3 This solid cord is then hollowed out apoptosis into neural tube 4 Spina bi da is the most common spinal cord defect 7 hmmm 3 Differentiation ofthe Neural Tube p 398 a The Three Levels of Neural Differentiation 1 Anatomically the tube bulges and constricts to form the various regions of the brain and spinal cord 2 At the tissue level the cells rearrange to form layered structures 3 At the cell level the various neurons and glia differentiate 4 The chick brain expands 30fold in 3 days E3E5 a Mostly due to uid pressure in lumen 7 drives differentiation b Constrictions are due to expansion of nonneural tissues 1 Separates brain from cord b Along the AnteriorPosterior Axis 1 The rst 3 anterior bulges start before posterior neural tube is done a Proencephalon will give rise to the forebrain b Mesencephalon will give rise to the rnidbrain c Rhombencephalon will give rise to the hindbrain 2 The secondary anterior bulges start around nish at the back end a The proencephalon divides into cerebrum and visual systems 1 The optic vesicles extend laterally from 2 The telencephalon will become cerebral hemispheres 3 The diencephalon gives rise to visual systems b The mesencephalon doesn t subdivide 7 stays the rnidbrain c The rhombencephalon starts with two bulges 1 The myelencephalon gives the medulla oblongata and the metencephalon gives rise to the cerebellum 2 Keeps forming bulges rhombomeres where speci c nerve mm 7 MC 3 AnteriorPosterior Patterning is Controlled by Hox Gene Expression b The DorsalVentral Axis 1 Both brain and spinal cord have signi cant dorsalventral structure a Cerebrum has siX layers b Spinal cord has input output intemeurons 2 Two sources of information regulate dorsalventral patterning a Ventral signal is sonic hedgehog from the notochord b Dorsal signal is TGFB family proteins from the epidermis 3 Sonic hedgehog induces medial hinge cells to become oor plate a Yet another secondary organizer 4 TGFB family proteins induces closure sites to become roof plate a Yet another secondary organizer 4 Speci cation and Differentiation ofNeurons p 410 442 a Neuronal Development 1 Induction and Patterning 7 Progressive Speci cation 2 Birth and Migration of Neurons and Glia a We have 100 billion neurons and a trillion glial cells b Ependymal cells line the inner tube and give rise to both 3 Dendrite Development a Average cortical neuron makes 10000 connections b At birth our neurons have a few or no dendrites l The rst year sees nearly all connections made 4 Axon Development a Growth cone and path nding 7 cell migration on a leash b Actin at the tips and tubulin giving extension 1 Remember hinge cells c Myelination 1 Cell wrapping for conduction 2 Oligodendrocytes in CNS Schwann cells in PNS 3 Multiple sclerosis is a disease of myelination 5 Synaptogenesis a Structure formation b Neurotransmitter development 1 Transcriptional control of enzyme pathway eXpression b Progressive Speci cation of Neurons 1 Speci cation of Neural Fate vs Glial or Epidermal a Occurs through the deltanotch pathway 2 Speci cation of Neuronal Type a Occurs due to position in neural tube on cell birthday 1 Cells of ventrolateral margin become motor neurons 2 Cells from dorsal position become interneurons b Position relative to the notocord and the oor and roof plates 1 Motor neurons need sonic two hedgehog signals 3 Target Speci city a Occurs due to order of cell birthday b First cells born differentiate and secrete retinoids c The neXt wave must migrate through them 1 The signal changes limprotein eXpression 2 Transcription factors related to hoxproteins d Before axon is sent out it knows its target 1 First wave medial cells innervates ventral muscle 2 Second wave lateral cells innervates dorsal muscle c Axonal Guidance 1 Selection ofthe Road a Permissive cell adhesion to extracellular matrix 1 Laminin guides growth cones 2 Fibronectin guides cell bodies b Repulsive adhesion by ephephrins and semaphorins c Permissive and repulsive soluble agents netrins d Combinations are the reality 7 remember summation 2 Selection ofthe Town a Permissive axon adhesion by ephephrins and cadherins b Permissive dendrite adhesion by semaphorins c Chemotactic agents 7 neurotrophins 3 Selection ofthe Address a Competative synaptic nalization 1 All junctions start with two or more connections 2 Low synaptic activity losers move on or b Differential survival 7 apoptosis is common d Behaviors and Neuronal Development 1 HardWired Behaviors a E19 chick s heart rate increases when they hear a distress call b Just hatched chick hides when exposed to hawk shadow 2 Neuronal Plasticity a Experiences change patterns b Retinal ganglion axons compete again when eyes open B The Neural Crest The cells that develop at the top of the neural folds from a combination of cells speci ed for both neural and epidermal fates are some of the most fascinating in all of Biology They are so unique in their development that some think they should be designated a fourth germinal layer and the vertebrates separated from the rest of the deuterostomes echinoderms tunicates and lancelets 7 seems reasonable Cristata they think we should be named 7 the family of the neural crest So what s so remarkable about these cells They pour off the top of the neural folds in great numbers migrate long distances and differentiate to form an amazing array of specialized tissues throughout the organism Without them we would have no head or face no peripheral nervous system no coloration no adrenal medulla and no integrated control of the blood vessels In short we would be 7 echinoderms 1 Organization ofthe Neural Crest p 427 a Regional Organization migration starts anterior and moves posterior 1 Cells above the forebrain and midbrain migrate into the head 2 Cranial neural crest cells go through pharyngeal arches from above hindbrain 3 Cardiac neural crest is the dorsal portion of the cranial but is gaining its own regional designation as we learn of its importance 4 Trunk crest migration occurs over the spinal cord of the embryo 5 Vagal anterior and sacral posterior portions also being rede ned b Commitment to Speci c Cell Fates 1 Initial speci cation is due to position as seen above a Dorsolateral Hinge Points eXposed to BMPs and Wnt6 b Transcription factor FoxD3 is required to become crest cells c Transcription factor Slug is required for epithelial to mesenchymal transformation and migration 2 Secondary speci cation occurs in the migration path a The path shapes the cell fate and the migration shapes the path 3 Determination apparently occurs at the nal destination 2 The Fore and Mid Brain Neural Crest a Not much has been reported about the fates of these cells 1 Most appear destined as neural and glial components of the brain 2 Probably contribute to the cranium and its derivatives in the face 3 The Cranial Neural Crest p 434 a The head and face are the result of neural crest development 1 These are the most anatomically sophisticated structures in the body 2 Contributions include neurons glia cartilage bone and melanocytes a Responsible for evolution of jaws teeth facial cartilage b Only the cranial crest retains ability to form bone and cartilage b Position along the hindbrain determines initial speci cation 1 The hindbrain is split into rhombomeres over the pharyngeal arches 2 Cranial crest cells migrate from rhombomeres 16 a Cells from RlRZ migrate through rst pharyngeal arch 1 Form jawbone earbones face bones b Cells from R4 migrate through second pharyngeal arch 1 Form earbones hyoid cartilage of neck c Cells from R6 migrate through third and fourth arches 1 Form thymus thyroid gland parathyroids d Cells from R3 and R5 must choose a group on either side c Innervation of the sensory placodes occurs in the second migratory wave 1 The sensory placodes also form from the epidermalneural border a Include the sensory apparatus for the nose ears and taste buds b Also the lens of the eye 2 The placodes must form neuronal connections to the hindbrain a The sensory neurons of the great nerves of the head and neck b The facial glossopharyngeal and vagus nerves 3 A second wave of neural crest migration goes dorsally a These cells become glia in the track of the axons above b They physically form the migratory surface the axons follow 4 The Cardiac Neural Crest p 441 a The posterior or caudal portion of the cranial neural crest l Rhombomeres ve and siX and even over the rst three somites b First known role in the heart was the endothelium of the aortic arch arteries 1 The heart forms right beneath the pharyngeal arches 2 The rst vessels formed take blood from the heart into the arches 3 All other vessels have endothelium derived from mesoderm c Also provide cells to control septum between the aorta and pulmonary artery 1 Shunts blood to the aorta when lungs are still unnecessary 2 Failure of neural crest cell migration gives persistent truncus arteriosis d More recently we have found them in the smooth muscle in the out ow tract 1 Again all other vessels have smooth muscle derived from mesoderm 2 At rst it was surprising but now makes perfect sense a The baroreceptors that inform brain of blood pressure are here b The smooth muscle that control blood pressure are here c The paths for axon migration to the hindbrain are here 5 The Trunk Neural Crest p 429 a Organized anteriorposteriorly along the somites 1 Structures that form the bone and muscle of the spinal cord 2 Mesodermal structures found only in the embryo b The two major migration pathways 1 The dorsolateral pathway a These cells are fated to become melanocytes 1 Travel between the epidermis and the dermis 2 Cut holes in the epidermal basal lamina and colonize a Colorize the skin keratinocytes and hair 2 The ventral pathway a Cells can become 1 Sensory neurons dorsal root of the spinal column 2 Sympathetic postganglionic neurons 3 Adrenomedullary cells 4 Schwann cells 6 The Vagal Sacral Neural Crest a Anteriormost and posteriormost portion of the trunk neural crest l Somites 17 and somite 28 b Form the parasympathetic ganglia of the gastrointestinal tract 1 Required for peristaltic movement 2 Also required for control of blood ow to the region 7 Mechanisms ofMigration and Differentiation are Linked a Growth factor signals second messengers and transcription factor responses 1 Growth factor binding to receptors causes progressive speci cation a Initial neural crest speci cation is by FGF and Wnt b EMF 4 and 7 then enter the picture and promote EMT 2 Second messengers promote the nonnuclear changes that are needed a Rho kinases cause the cytoskeletal changes of movement b Rho signals or some other pathway break adhesions 3 Transcription factors signal the wholesale changes in gene eXpression a This is where FoxD3 and slug come in b Extracellular guidance cues 1 Positive guidance a Integrins bind and allow cell movement along proper path b Thrombospondin bronectin tenascin some collagens active c Integrin X461 found on migrating cells binds several of these d ephs and ephrins show the correct road for some cells 2 Negative guidance a ephs and ephrins show the edge of the road for others b Neural crest cells have the eph the wrong cells the ephrin 3 Target cells release soluble chemotactic factors a Stem cell factor guides melanocytes into skin c Lose the eXpression of key molecules and stray from the path and you die d Differentiation 1 Many neural crest cells are pluripotent a Parasympathetic cholinergic neurons form from vagal region b Sympatheic adrenergic neurons form from thoracic region c Transplant them and the cells will switch neurotransmitters d Initial speci cation produced enzyme pathways for both 1 Final destination dictated which pathway survived 2 Not all though some populations are committed at migration a Still a lot of work to do here b Some work suggests the ratios of Wnt and BMP decide 3 Final differentiation occurs at destination for most neural crest cells a The heart secretes LIF which can convert adrenergic neurons into cholinergic neurons b Several tissues secrete BMPZ which promotes adrenergics c Glial growth factor GGF shifts neurons to glial fates 20 d Endothelin3 promotes adrenergic differentiation unless found together with Wnt s and then they become melanocytes e Cells that enter the region of adrenal glands become sympathetic neurons unless close enough to see glucocorticoids which shifts them to an adrenal medullary fate C Development of the Skin The skin is a complex organ made up of three layers the ectodermally derived epidermis the surface that you think of as skin and beneath that the mesodermally derived dermis and subdermal connective tissue The epidermis itself is compleX consisting of cells in a variety of stages 7 actively dividing differentiating committing suicide and even hanging around after they re dead There are also many specialized cells and structures in the skin that are derived from the same stem cells including hair feathers and scales sebaceous and sweat glands mammary glands and teeth Surprisingly the skin is a very interesting place 1 The Origins ofthe Epidermis Proper p 416 a After neurulation there is a single cell layer remaining in ectoderm b This layer soon forms a second layer 1 The inner layer will go on to form the epidermis 2 The outer layer or periderm is temporary covering a It is shed in the embryo as soon as the inner layer gets going c The inner layer or basal layer is a germinal epithelium like ependymal cells 1 Gives rise to all cells of the epidermis 2 The rst step down the pathway is the formation of spinous cells a Forms a second dividing layer on top of the basal cell layer b Two layers combined are the epidermal stem cells c Called the Malpighian layer 3 The second step is the formation of granular cells a Called that because they store granules of keratin b These cells have withdrawn from the cell cycle c They continue to make keratin and migrate outward 21 4 Matuiing granular cells become keratinocytes a Make huge amounts of keratin and cellcell connections b As they mature they quit supporting themselves metabolically c When they die they hang around in the corni ed layer 5 An interesting event is the migration of neural crest cells into the epidermis to form melanocytes the melaning producers of the skin a They set up shop and pass melanosomes to keratinocytes b The corni ed layer still has fading melanosomes at the end d This process continues from neurulation until death 1 In the normal adult human a Malpighian cell is born takes eight weeks to reach the corni ed layer and then two weeks to be sloughed off 2 Psoriasis is linked to this process through TGFoc a TGFoc stimulates basal cell division b OvereXpression leads to rapid turnover and dead keratinocytes last only two days in the corni ed layer 2 The Origins of Specialized Cells and Cutaneous Appendages p 418 a All of these structures form from basal cells in the epidermis b Basal cells are induced by the dermis to differentiate down a new path 1 Mesodermal dermis interacts with ectodermal epidermis a Induction between cell types is a common theme 2 Placode formation a Fibroblasts of dermis condense under control of Wnt s b Signal basal cells by FGF 10 to form columnar epithelium divide and then growing placode sinks into upper dermal layer 3 Most of what we know is known about hair formation p 419 a Probably somewhat similar for other structures 22 b Fibroblasts condense further to form a dermal papilla 1 Node of cells under sunken epidermal cells 2 This turns the structure into a follicle c Drives a further increase in the rate of division in basal cells 1 Promoted by autocrine sonic hedgehog 2 Also release BMP s to stop neighbors from joining d Epidermal cells differentiate into keratinocytes of hair shaft 1 These are actually dead cells like comi ed layer 2 Three types of hair shaft a Lanugo 7 embryonic thin and short b Vellus 7 preadolescent silky and short c Terminal shaft 7 long thick and pigmented d Male Pattern Baldness follicles make vellus e Follicular bulb develops in basal epithelia l Basal cell stem cells to regenerate follicle 2 Melanoblast stem cells to regenerate color f Sebaceous bulb develops in basal epithelia l Secrete sebum onto the shaft and skin 23 B10 127 Vertebrate Embryology Fall 2004 Lecture Outline for Section 3 IV Development of the Mesoderm and the Endoderm In this section we will look at the development of the other two primary germ layers The ectoderm starts on the top surface so next we ll look at the middle layer or mesoderm and then the bottom layer or endoderrn It is often easier to look at the tissues that these latter two structures form simultaneously This is true because while they form quite different cell types many adult tissues contain derivatives of both Many of the same concepts that we saw in our discussions of the ectoderm will also be obvious here such as induction events between germinal components transfer of organizing power and progressive speci cation A key difference between these layers and the ectoderm is that they start as a loose mesenchymal migration of cells thus their plates are quite different For ease of Visualization we ll again use the nice discoidal avian embryos as the primary model in our discussions just keep in mind that the same things occur in our curved embryos it s just way harder to draw on the board A The Paraxial Mesoderm The primary distinctions in mesodermal tissues are their position relative to the midline ParaXial means along the axis or near the midline and thus along the developing neural tube This distinguishes it from regions of the mesoderm farther out 7 the intermediate mesoderm and the lateral plate mesoderm 1 The Three Subdivisions ofthe Paraxial Mesoderm a The Prechordal Plate Mesoderm 1 Forms the connective tissue and musculature of the head b The Chordamesoderm 1 Forms the notochord c The somitic dorsal mesoderm or paraXial mesoderm proper 1 Forms the somites which give rise to a Vertebrae and ribs b Dermis of the skin of the back c Skeletal muscle of the back and the body walls 1 Skeletal muscle of the limbs 2 The Formation of the Somites p 467 The main mesoderrnal components that form along the developing neural tube are the somites We used them in the last section to count out our position along the neural tube but they are much more than place markers They are the source of the noncranial axial skeleton and of the musculature of the thorax abdomen tongue and limbs They also provide the cartilage of the spinal cord and ribs and the dermal layer of the skin of the back a The timing and periodicity of somite formation 1 As the primitive streak moves forward a Mesenchymal cells migrate to form the middle layer b Simultaneous with start of neural tube formation c Presomite mesoderm due to noggin antagonism of BMP4 2 As the primitive streak moves backward a Henson s node secretes FGFS goes away as node does b FGFS blocks Lunatic Fringe protein expression c Lunatic Fringe TF causes expression of Notch d Notch causes expression of Hairyl in 90 second waves e Each wave leads to a new somite forming b Somite epithelialization l Mesenchymal to epithelial transformation c Speci cation of the somite along the AnteriorPosterior axis 1 Somites that form cervical and lumbar vertebrae don t form ribs 2 Somites that form thoracic vertebrae also form ribs 3 Primarily Hox gene dependent like the neural tube d Determination of the derivatives of the somite l The sclerotome forms in the ventralmedial portion of the somite a Forms the cartilage of the vertebrae and ribs b Undergoes a reversal to mesenchymal cells 2 The myotome forms in the two lateral regions of the somite a Form the muscle in that region of the embryo b Divides into two layers the dermamyotome l Myoblasts close to neural tube form deep back muscle 2 Myoblasts away from tube give limb tongue abs 3 The dermatome forms in the center of the myotome a Can t tell them apart until dermis cells migrate away b Undergoes a reversal to mesenchymal cells e The fate of the notochord l Wherever the sclerotome forms a vertebral body the notochord apoptoses 2 In between these cells contribute to the intervertebral discs a These are the discs that slip in back injuries 3 Myogenesis The Development ofMuscle p 473 a Muscle Cell Fusion 1 Single nucleated cells are called myoblasts 2 Our muscles are made up of multinucleated myotubes a These result from the fusion of a few to many myoblasts b They align neXt to each other and dissolve their membranes 3 They must leave the cell cycle to do this a With a particular growth factor milieu in place they ll divide b When they migrate into nal destination they lose it and fuse 4 Fusion is cadherin dependent and not species dependent a As long as they have the right cadherin rat and mouse will fuse 4 Osteogenesis The Development ofBone p 474 a Three cell lineages give rise to bones l Cranial neural crest gives face bones 2 Lateral plate mesoderm gives bones of the limbs 3 Somites of the paraXial mesoderm give the aXial skeleton b Two methods of bone formation 1 Intramembraneous ossi cation a Mesenchymal progenitors are converted directly into bone 2 Endochondral ossi cation a Mesenchymal cells go through a cartilage phase rst c Intramembraneous ossi cation of at bones l Migrating neural crest or paraXial mesoderm cells condense into nodes 2 Condensation leads to osteoblast formation bone cell commitment a Osteoblasts secrete collagenbased matrix specialized for CaH b Attachment to their own product gives nal differentiation 1 Osteocytes 3 Calci cation proceeds outward from osteocytes a Makes more mesenchymal cells condense 7 can happen fast d Endochondral ossi cation of long bones l Migrating paraXial or lateral plate mesoderm cells commit to cartilage 2 Mesenchymal cells condense into nodes of prechondrocytes 3 Rapid proliferation produces cartilage model of the bone to come a Produces the exact shape of the future bone 4 Chondrocytes hypertrophy and change their metabolism a Causes a secretion ofa calci able matrix b Also cause a little thing called apoptosis 5 Cells hanging out around the cartilage model become osteoblasts a Invade model and calcify the matrix b Accompanied by chondroclasts 7 eat the dying e Bone remodeling l Osteoclasts differentiate from macrophage progenitors 2 Reside in bone and balance activity of osteocytes B The Intermediate Mesoderm The portion of the mesodermal layer just lateral to the paraxial mesoderm is the intermediate mesoderm The main claim to fame of this tissue is the formation of the urogenital system the kidneys gonads and their respective duct systems We ll save the gonads for a later discussion of sexdetermination might as well follow the book for once The formation of these organs is a highly informative introduction into the formation of organs in general As you ll see it is not surprising that such a relatively large area of embryonic tissue is devoted to such a seemingly small pursuit 1 The Speci cation ofthe Intermediate Mesoderm p 478 a Develops next to paraxial mesoderm which instructs it to form kidneys 1 Cut the tissue connection 7 no kidneys will form 2 Coculture of the two tissues 7 kidneys will form 3 Don t know what the signaling molecule is yet 2 Progression of Kidney Types p 479 a The kidney is very complex 1 The nephron has over 10000 cells of at least 12 different types a Each is exactly located to the appropriate spot or the organ fails b Three stages of development the latter persists as the functioning organ 1 The pronephros forms very early in development a Arises ventral to the most anterior somites b Mesenchyme of the intermediate mesoderm condense into tubules c In embryos of sh and amphibians it actually works for excretion 2 The mesonephros forms in the slightly more advanced embryo a The pronephiic duct system degenerates by apoptosis b New intermediate mesoderm mesenchyme recruited for new ducts c Filters blood and forms urine in some but not all mammals d Most of it also degenerates by apoptosis e Two major parts of the mesonephros are retained into adulthood 1 It appears to be the source of all hematopoeitic stem cells 2 Parts remain as the vas deferens and associated ductwork 3 The metanephros a The very posteriormost region of mesonephros becomes kidney b Epithelial ducts and metaneph1ic mesenchyme do the organ dance also called Reciprocal interactions of the developing kidney p 481 a Step 1 Speci cation of the metanephric mesenchyme b Step 2 Mesenchyme induces mesoneph1ic duct to bud out c Step 3 Survival and epithelialization of mesenchyme caused by ureteric buds d Step 4 Nephron differentiation from epithelialized mesenchyme cells e Step 5 Branching of ureteric bud f Step 6 Formation of the nal pattern of glomeruli and collecting ducts C The Lateral Plate Mesoderm Now here is a tissue that I ve come to know and love Ah the lateral plate mesoderm 7 the source of the cardiovascular system The heart and the blood vessels are the rst organ system to become fully functional The normal development of which is essential to all development beyond gastrulation Once the cell layers get to a certain thickness no life is possible without the internal delivery of nutrient from the yolk or mother 1 The Structural Divide in the Lateral Plate a The Somatopleure b The Splanchnopleure 2 The Development of the Heart p 492 a A Little Anatomy Review 1 The heart is a muscular hollow ball about the size of your st 2 Four chambers contract synchronously 7 two atria two ventricles a The right and left atrium contract together to ll ventricles b The right and left ventricles contract together to send blood out 1 The right side lls the lungs the left the rest of the body 3 The vena cava ows into the right atrium 4 The pulmonary artery out of the right ventricle the aorta out of the left 5 Valves form between atria and ventricles ventricles and arteries b Speci cation and Migration of Heart Progenitors l The heart forms as two tubes in the splanchnic mesoderm a Some of the rst cells into the streak right behind the node b Cardiogenic mesoderrn is mesenchymal cells bilateral to notochord l Progenitors for muscle valves endothelium Purkinje bers 2 Speci cation is from endodermal induction 3 Migration of speci ed cells to the anterior is along the endodermal lining a Epithelial condensation then follows 4 The inward folding of the foregut endoderrn then brings the two tubes close a Interestingly zebra sh have an active migration of cardiac cells c Determination and Fusion of Cardiac Primordia l Endocardium separate out from epithelium and then reepithelialize a They migrate into the center of each tube to line the muscle 2 Tubes come together and fuse at 29 hours in the chick 3 weeks in humans a Both muscle and endocardium b Spontaneous contractions begin before the tubes are fully fused 3 Unfused portions at each end become presumptive in ow and out ow tracts d Looping of the Heart Tube and Chamber Development 1 A very widely studied phenomenon 7 check it out if you re curious p 495 a Handl and Hand2 transcription factors are key regulators b Looping is how the ventricles and atria move into superioranterior 2 Myocardium induces endocardium to EMT and make endocardial cushions a Cushions separate the tube in half b Two septa then grow toward cushion to partition the atria 3 The Formation of Blood Vessels p 500 a Vasculogenesis de novo formation of endothelium 1 Blood islands throughout the splanchnic mesoderm c Angiogenesis budding and eXtension of eXisting blood vessels d Secondary Vasculogenesis in the coronary arteries e Invasion and Replacement 4 The Development of Blood Cells p 505 a Stem Cells Revisited b Two Stage Hematopoiesis c Progressive Speci cation l Pluripotential Hematopoeitic Stem Cell 2 LineageRestricted Stem Cells 3 Hematopoeitic Inductive Microenvironments D The Endoderm This last of the three germinal layers starts out at the bottom after gastrulation and winds up on the inside of the organism This is due to the inward folding events that we discussed brie y in heart development above The primary tissues formed by the endoderm are l the gastrointestinal tract and its organ derivatives the liver gallbladder and pancreas 2 The airways of the bronchial tubes and lungs and 3 The extraembryonic membranes that provide the developing embryo with nutrient waste and gas exchange The endoderm also plays a key role in the induction of the mesodermal layer as well as many of its derivative tissues such as the notochord heart and blood vessels 1 Formation ofthe Primary Endodermal Tube the Primitive Gut p 511 a Development is anterior to posterior like everything else 1 Budding from this tube gives the GI tract organs and airways 2 The rst distinctions are the separation of foregut and hindgut 3 The tube starts out covered and closed by ectoderm 7 the stomodeum a This ectoderm is still in contact with neural ectoderm b The stomodeum forms Rathke s pouch and glandular pituitary c Nearby neural cells become infundibulum and neural pituitary b The most anterior structure is the pharynx remember the pharyngeal arches 1 We produce four pairs of pharyngeal pouches with the arches between a The rst pair becomes auditory canals and eustachian tubes b The second pair gives the walls of the tonsils c The third gives the thymus and one pair of parathyroid glands d The fourth pair gives the other pair of parathyroid glands l The oor beneath buds off into respiratory tract 2 We also form a small tissue structure under the second pair of arches a Forms the thyroid gland in combo with mesodermal cells 2 The Gastrointestinal Tract and its Derivatives p 511 a Constrictions in the tube form esophagus stomach small and large intestine 1 Different regions are induced by different splanchnic mesoderrn 2 Mesodermal mesenchyme recruited to form smooth muscle layer 3 The back end also starts covered by ectoderrn 7 cloacal membrane b The derivative organs 1 The liver forms much like the kidney 7 buds induced by mesenchyme a The key mesenchyme is heartforming region b Mesenchyme also induces branching and differentiation c The gallbladder forms as early drainage duct but remains d Interstingly the liver induces proepicardial formation in turn 2 Two distinct endodermal buds fuse to form pancreas a Notochord is key inducer heart cells seem antogonistic 3 The Respiratory Tract p 515 a Bud extends from pharyngeal oor as laryngotracheal groove 1 The tube bifurcates into paired bronchi and lungs 2 Mesodermal mesenchyme implicated here as well a Also recruits smooth muscle layer b Alveolar development is last to develop in terrestrial animals 1 Surfactant is nally secreted as late as 34 weeks in humans 4 The Extraembryonic Membranes of Terrestrial Vertebrates p 517 a The embryo must avoid dessication 7 forms the amnion 1 Secretes amniotic uid b The embryo must exchange gasses from an enclosed place egg or uterus 1 Forms the chorion a The membrane inside the shell in reptiles and birds b The placenta in humans c The embryo must remove waste 7 forms the allantois l A membraneous sack that holds waste until hatch or birth 2 Ours is vestigial pigs use it tremendously d The embryos gotta eat 7 forms the yolk sac l surrounds the entire yolk connects to the midgut and blood E Development of the T etrapod Limb The limb is a pretty amazing thing It always forms as two mirror image pairs directly opposite each other on the sides of the trunk It changes from the shoulder or hip to the fingers or toes proximal distal axis It changes from the thumb or big toe in front to the pinky nger or little toe in the back anterior posterior axis It also changes from the knuckles to the palm or bottom of your foot dorsal ventral axis How does such a complex pattern form so regularly look around it s pretty remarkably consistent This process is a microcosm of embryonic Pattern Formation development of coordinate structure in four dimensions of space and time 1 Speci cation ofthe Limb Bud Getting It All Started a Speci cation along the animals anteriorposterior axis 1 Forelimb buds always form at anteriormost Hox d6 in midline 2 Mesoderm in limbforming region then recruits somitic myoblasts 3 Retinoic acid from Henson s Node is critical a Remove tadpole s tail give RA 7 get several legs b The limb eld has complete potential for all limb components 1 Transplantation gives ectopic limbs 2 Separation gives multiple limbs c Accumulation of lateral plate and paraxial mesoderm beneath the ectoderm 1 Bones will come from lateral plate muscle from paraxial 2 Bud is a subectodermal bulge ofmesoderrn 2 Generation of the Proximal Distal Axis a Generation of the apical ectodermal eld 7 organizing power 1 Mesodermal FGFlO causes adjacent ectoderm to form ridge 2 Ectoderrn in turn stimulates mesodermal proliferation 3 The mesoderm has competence for limb cell types ectoderm signals b The Progress Zone carries the proximaldistal information 1 Progress Zone is endcap mesoderm and ectodermal ridge 2 Has the information for humerous radiusulna digits a Transplantaion of older PZ gives older cell types b Not sure how 3 Generation of the Anterior Posterior Axis a Generation of the Zone of Polarizing Activity 7 more organizing power 1 The ZPA arises very early in limb bud stage a From a small patch of mesoderm in posterior 2 Sonic hedgehog is its power molecule a Shh release causes gradients ofBMPZ and BMP7 b Gradients cause interdigital mesoderm to specify anterior digit 1 Then they apoptose 4 Generation of the Dorsal Ventral Axis a Controlled by the different ectodermal tissues close to the mesoderm l Wnt s from ectoderm cause mesoderm to form pads or knuckles 2 Mesoderrn appears to cause ectodermal changes F Sexual Development This is an area of Developmental Biology that often surprises people We tend to be familiar with the chromosomal determination of sex at least in mammals and of the hormonal in uences that drive the development of secondary sexual characteristics during puberty These are the beginning and the end of the process Chromosomal determination starts at the point of conception and the development of secondary sexual characteristics occurs well after birth During the embryonic period some rather odd things are known to happen 1 Chromosomal Determination of Sex a Mammals 1 Females have a matched pair of sex chromosomes XX a Haploid sex cells eggs have an single X 2 Males have an unmatched pair of sex chromosomes XY a Haploid sex cells sperm have an X or a Y 3 Offspring pick up one from each parent b Birds 1 Females have an unmatched pair ZW 2 Males have a matched pair ZZ c Bees 1 Females are fertilized diploids 2 Males are unfertilized haploids d Flies 1 Determined by the numeric ratio of X and somatic chromosomes 2 Development ofthe Gonads a Develop from the intermediate mesoderm near the developing kidney b Early development is uniform in males and females indifferent stage 1 Selected mesenchyme condenses into sex cords a Development is by mutual induction with mesenchyme b Forms the Mullerian duct by interconnection of cords c There is no default stage in humans 1 Need two X s to develop functional ovaries a With one X ovarian follicles develop but can t be maintained 2 Need two Y s to develop testes a Y carries a gene SRY that provides testes determination d Gonad development prepares for the nal differentiation of germ cells 1 Granulosa and thecal cells are speci ed in females 2 Leydig cells in males 3 Development ofthe Primordial Germ Cells a Germ line cells are determined in the epiblast during cleavage phase 1 In the posterior portion near the start site of the primitive streak b They have to walk to the gonads 7 in humans it can take weeks 1 Migrate through the hind gut in a little row 2 Reach the gonads determined differentiate there based on hormones 4 Development of Secondary Sexual Characteristics a EXtemal genitalia internal ductwork hair breasts larynx you know the list b All of this is dependent on the gonadal hormonal milieu 1 Female characteristics dependent on ovarian estrogen eXpression a Mullerian duct becomes uterus oviducts upper end of vagina b In puberty all the rest of the effects kick in 2 Male dependent on testosterone and Mullerian Inhibiting Substance a Mullerian duct degenerates b Penis seminiferous tubules and ducts develop 1 Vas deferens epididymous are mesonephric remnants c In puberty all the rest of the effects kick in B10 127 Vertebrate Embryology Fall 2004 Lecture Outline for Section 1 The goals of this class are two fold 1 To study the long established anatomical eld of Vertebrate Embryology and 2 To place this information into context within the rapidly growing field of Developmental Biology of which Embryology is an important part For many of you this is a topic that you ve read or heard a fair bit about but you don t know the whole story For others it is something completely new Whatever you have learned be it a few years ago last semester or even yesterday the one thing I can guarantee is that the field has already changed Understanding the development of an organism from a fertilized egg cell to an old or senescent adult is one of the most complicated problems ever tackled by hum ans The genome project is child s play by comparison The field encompasses all of biology so much so that many scientists have no idea that their work in Molecular Biology or Anatomy may some day revolutionize our understanding of Developmental Biology 1 Embryology is Part of Developmental Biology A Complexity that Bends the Mind 1 The big picture of Developmental Biology is trying to understand and integrate the many thousands of events that transform two haploid gametes into a reproductively capable adult made up of as many as 10 trillion cells And beyond that through the natural or diseaseinduced senescence that produces death 2 Embryology is the study of the events prior to birth or hatching in vertebrates prior to the emergence of plants from the seed or prior to the larval stage in metamorphic organisms such as arthropods and echinoderms a The similarity of processes between species has made this area of research heavily dependent on these model organisms 3 Postnatal Child and Adolescent Development Growth and Sexual Maturation are some of the disciplines that study the transition from birth to reproductive activity 4 The adult was long thought of as the ultimate expression of phenotype and the time when development of the organism stopped but more and more developmental processes are seen to be active in the adult a Stem Cells One of the sexiest topics in all of biology Cells in the adult that retain the embryonic ability to differentiate into more than one cell type 7 maybe any cell type 1 Ifwe could just control it b Healing requires quiescent cells to migrate acquire contractile abilities they don t normally exhibit and make huge amounts of extracellular matrix molecules c Cellular Immunity Not only do these cells all arise from stem cell populations in the bone marrow but they can change their expression to adapt to each new invader d Tissue Regeneration Essentially involves the switching on of the entire developmental process for a lost limb or organ many invertebrates can do this as can a few vertebrates 5 Ageing research has grown tremendously over the last two decades a Senescence the decline in cellular activity and even the number of cells in organs and tissues appears to be as natural a developmental process as differentiation or growth b One of the most fascinating discoveries of the last decade or two is that our biggest human killers are diseases of developmental abnormalities ancer 2 Coronary Artery Disease B The History and Contributions of Embryology 1 Classic Embryology This is Your Daddy 3 Embryology 7 This is where it all started The art of opening the eggs larvae or uterus of a huge variety of organisms taking them at precise times day after day and observing and recording what you see in exacting detail Some of the greatest discoveries ever were made with little more than a bad microscope a steady hand and an active mind We ve got better stuff but some of these guys were good a So who started all this Aristotle published the Generation of Animals in 350 BC describing the daily examining of embryos from a whole bunch of animals mostly chick b The dark ages left little progress for 2000 years Harvey published the next great work On the Generation of Living Creatures in 1651 Aristotle was his personal hero He also worked primarily on the chick embryo c In 1672 Malpighi published the rst microscopic account of chick development d Inheritance theory In the late 1700 s philosopher Emanuel Kant working with a Biologist buddy named Blumenbach in an effort to explain racial descent postulated that epigenesis must occur from an inherited force or instructions Unbelievably close to what we think now e Evolution and Embryology Reformist Germany in the early 1800 s plants new seeds evolution Embryologists have played a central role in the controversy that continues through today l Pander only worked a few years but published a brilliant book in 1817 showing the three germ layers and describing their inductive interactions 2 Rathke worked 40 years comparing embryos of many different species The most classic was the pharyngeal arches present in all vertebrates becoming gills in sh but jaws and ears in mammals 3 von Baer also spent his life working in Comparative Development Developed the rst laws of evolutionary embryology which said that early embryos of vertebrates are very similar Common structures develop first skin and limbs and specialized structures scales hair wings fins come later until the embryos can be told apart 4 Evolutionary theory is fully established in 1859 by Darwin s unparalleled book The Origin of the Species Darwin extended von Baer s laws to all animals saying that related embryonic forms directly give related species 2 Experimental Embryology By the turn of the 20 h century people begin to collect and manipulate embryos Asking speci c questions and working under the rigors of the scienti c method The rate of change in our understanding of embryo development begins to increase exponentially Still does a Fate mapping and cell lineage analysis Naturally pigmented cells vital dyes radiolabels the chickquail chimera 3 Genetic and Molecular Embryology Combining genetic and molecular information with classic and experimental techniques is the beginning of our true understanding of the embryo We are many lifetimes from that objective but the speed with which our skill and knowledge are growing in this area give the eld an aura of excitement a Mendel e great work in trait transmission in plants is rediscovered did his work in the 1860 s in the 1920 s b DNA structure in the 1950 s Watson and Crick Linus Pauling Amazingly all known cells store their hereditary information in doublestranded DNA c The technical revolution PCR transgenics bioarrays genome project C Where are we now and what does the future hold 1 What do we know right now What questions are we capable of asking today What will we learn tomorrow How will we store and retrieve all of this information How will we use it No one knows the answers to these basic questions today and there will be much much more information and complexity tomorrow Some day the differences between species evolutionary relationships teratogenic mechanisms congenital diseases heart disease cancer 7 all will be understood and addressable by people around the world Do you think humans will be ready for this knowledge II Mitosis and Meiosis in Vertebrate Embryology A The Mitotic Cell Cycle in Development Once a vertebrate egg is fertilized that single diploid cell with two pairs of each chromosome must divide into two diploid daughter cells they in turn must divide into diploid daughters ultimately producing an adult organism composed of potentially trillions of cells Most cell divisions in the embryo are mitotic although as we proceed we ll see that mitosis can be varied in the embryo and meiosis also plays a very large role 1 Overview of the Mitotic Cell Cycle and Cell Division Diploid cells must duplicate the contents of their cytosol and nucleus prior to splitting to form two genetically exact daughter cells This is the process by which cells reproduce and increase their number a All vertebrate cells have a characteristic cyclic pattern to their mitotic cell division This cycle is closely regulated and quite predictable in timing 1 Interphase is the period in which a cell duplicates its DNA and makes the proteins it needs to divide 2 Mitotic Phase is the period in which a cell carefully divides rst its nuclear contents and then its cytosolic contents into the daughter cells b Mitosis produces exact genetic duplicates but not all cells are the same We ll talk a lot about asymmetric mitotic cell division in this class 1 Cell differentiation often occurs at the time of mitotic division 2 Withdrawal and Reentry to Cell Cycle a Embryonic cells start out in the mitotic cycle and some never leave 1 Gut endothelium immunological stem cells etc b Upon nal differentiation most somatic cells withdraw from the cell cycle 1 Liver cells muscle cells brain cells etc leave the cell cycle and perorm adult functions 2 Go is the designation of the nondividing cell 3 This is often permanent c For some of these cells a message can come along telling them to stop hanging out and reenter the cycle of cell division 1 Liver cells are a classic example 2 Dedifferentiation is a phenomenon of re expression of an embryonic phenotype that includes cell cycle gene expression 3 Inter ph ase a Gap 1 G1 rst gap in DNA synthesis is the time that a cell uses to make the mRNA and protein necessary for DNA synthesis 1 Need DNA synthase complexes repair enzymes histones etc 2 Each chromosome is a single DNA molecule Humans have 46 DNA molecules in our nucleus Two near matches of 23 distinct chromosomes b Sphase is the time required to synthesize exact copies of all chromosomes 1 Synthesis and error editing are the primary objectives 2 After Sphase we still have 46 chromosomes but they are composed of double the DNA in the form of two chromatids joined at the centromere 3 There would be 92 molecules of DNA 4 each of 23 different chromosomes if the chromatids weren t stuck together c Gap 2 G2 second gap in DNA synthesis is the time that a cell uses to make the mRNA and protein necessary for cell division 1 Need cytoskeletal proteins molecular motors metabolic enzymes etc 2 Kinetochores are re ned and nalized 4 Mitotic Phase a Mitosis mphase is the mechanism that a cell uses to separate its nuclear components into two nuclei Mitos is Greek for thread and refers to the condensed chromosomes that become visible during the mitotic phase 1 Prophase a Twin chromatids are condensed around histones remained joined at centromere kinetochore complex at centromere b Centrosomes move apart and begin to organize microtubules into spindle bers c Nuclear membrane disintegrates allowing spindle and kinetochore to intreract 2 Metaphase a Chromosomes align on equatorial plane with one of each pair of kinetochores attached to bers from opposite centrosomes b Chromatids remain attached at centromeres 3 Anaphase a Chromatids separate and move toward the centrosome they are attached to produce 92 independent human chromosomes 4 Telophase a Kinetochore bers disappear b Two new nuclear membranes form around chromosome sets c Chromosomes uncoil b Cytokinesis is the mechanism that a cell uses to separate its cytosolic components and its two new nuclei into two distinct membranebound cells 1 Begins in Anaphase 2 Results from actinomyosin constriction much like muscle 3 Membrane fusion forms two distinct cells B Meiotic Cell Division 1 Comparison of Cell Division in Sex Cells Meiotic cell division is the mode of division performed only by the sex cells of a plant or animal 2 Interphase a Gap 1 again makes the mRNA and protein necessary for DNA synthesis b After Sphase we still have 46 chromosomes but they are composed of double the DNA in the form of two chromatids joined at the centromere c Gap 2 again makes the mRNA and protein necessary for cell division 3 Meiotic Phase a Meiosis I l Prophase I a Twirl chromatids condense joined at centromere b Crossover occurs during condensation c Spindles begin to form nuclear membrane disintegrates 2 Metaphase I a Chromosomes align on equatorial plane with one of each pair of chromosomes attached to fibers from opposite centrosomes b Independent assortment of chromosomes occurs here c Chromatids remain attached at centromeres 3 AnaphaseI a Chromasomes paired chromatids move toward centrosomes 46 independent human chromosomes 23 each way 4 TelophaseI a Reverse of Prophase I b Cytokinesis I 1 Mostly the same c Some organisms have a short interphase between Meiosis I and Meiosis II d Meiosis II 1 Prophase II a Mostly the same 2 Metaphase II a Chromosomes align on equatorial plane with one of each pair of kinetochores attached to bers from opposite centrosomes 3 Anaphase II a Chromatids separate and move toward the centrosome they are attached to 46 human chromosomes 23 each way 4 Telophase II a Mostly the same d Cytokinesis II 1 Mostly the same III Gametogenesis A Spermatogenesis 1 Background a A Little History The Role of Sperm Only Recently Identi ed 1 Van Leeuwenhoek championed Preformism a Codiscovered sperm in 1678 b Thought they were parasites at rst 7 spermatozoa 1 The name means animals in the sperm c Later thought they contained fully formed humans 1 Codiscoverer Hartsoeker thought so too d Most people didn t buy it 7 too huge a waste of life 1 General consensus was that they were irrelevant 2 Prevost and Dumas believed they played an important role a By 1824 they had good scopes and cell theory b Claimed that sperm entered egg and provided material c No one believed them either 7 still thought them irrelevant 3 von Kolliker showed that the testes made sperm in the 1840 s a Still didn t think they contacted or entered the egg b He thought they inspired the egg to develop from a distance through some sort of electromagnetic interaction 4 Hertwig and Fol nally demonstrated spermegg fusion in 1876 a They watched the nuclei unite 128 years ago b Noted that only a single sperm entered any one egg c Used the sea urchin as we will next week b Structure and Function of the Mature Sperm l The sperm is designed to swim to the egg penetrate it s species speci c barriers and deliver a haploid nucleus to match that of the egg a It has a motorized transport in the form of a agellum l Centrioles tubulin and dynein 2 Mitochondria and ATP b It has proteins to identify itself and penetrate the egg 1 The acrosome 2 Species ID proteins on the acrosomal membrane c It has a nucleus containing a single set of chromosomes 1 Highly condensed chromosomes 2 Streamlined nucleus 2 New Idea a Paternal RNAs found in cleavage stage cells last year 2 Mechanisms of Spermatogenesis a Organization of the Mammalian Testes l The seminiferous tubules are the primary sperm producing structures a Testicular lobes contain many seminiferous tubules b Maturation occurs from the periphery towards the center 1 The most immature cells on the outer wall 2 The lumen of the tubule is a collecting duct 2 Cell types a Germ line cells 1 Spermatogonia a Form by mitosis and diVide by mitosis b Spermatogonia are stem cells 2 Spermatocytes a Form by mitosis and divide by meiosis b Daughter cells are joined by cytoplasmic bridges due to incomplete mitotic cytokinesis 1 pass molecules even organelles 2 both parents direct development 3 Spermatids a Form by meiosis and do not divide b Daughter cells are also joined by cytoplasmic bridges due to incomplete meiotic cytokinesis c Rounded amoeboid cells 4 Sperm a Mature from spermatids via spermiogenesis b Sertoli cells 1 Form a bloodtestes barrier 2 In fetus release antiMullerian duct hormone 3 Prepubeity inhibit division of spermatogonia 4 Postpuberty activate spermatogonia 5 Physical and nutritional support to germ cells c Interstitial cells 1 Reside between seminiferous tubules 2 Produce testosterone b Regulation of Spermatogenesis and Spermiogenesis 1 At puberty pituitary gland stimulates interstitial release of testosterone 2 Testosterone stimulates spermatogonia mitosis spermatocyte meiosis 3 Testosterone stimulates Sertoli cell activation of spermatids a Acrosome coalesces and nucleus rotates it away from lumen b Single centriole extends agellar microtubules into lumen c Nucleus condenses and most of cytosol is lost as polar body d Mitochondria are amassed in the neck region B Oogenesis 1 Background a A Little History 1 Discovery of the Mammalian Egg a Most invertebrate and vertebrate eggs were easy to nd b Harvey proposed that all animals came from eggs in 1651 c von Baer nally found a mammal egg in 1828 2 Spermatogonia are Stem Cells Oogonia are Not except for insects a Mammalian oocytes are formed long before sexual maturity b They are lost through ovulation and apoptosis c Menopause occurs when no more follicle are making estrogen b Structure and Function of the Mature Egg 1 The egg sjob is to pass on haploid DNA fuse withjust a single sperm provide nearly all of the essential starting materials for the embryo and provide some protection 2 The egg is huge compared to the sperm a Bird eggs are single cells that are packed with yolk b Sea urchin eggs are low yolk 10000 times the size of sperm c Must accumulate everything that will be needed 1 Conserves what it started with during meiosis 2 Actively absorbs and makes yolk etc 3 The cytoplasm of the oocyte is a great storehouse built during interphase G2 and meiotic prophase 1 Four sets of chromatids a Oocytes are Information Storehouses 1 Proteins signaling molecules transcription factors 2 Ribosomes and tRNA for making new proteins a some amphibian eggs make 1012 ribosomes by selective gene ampli cation of tandem repeats ll 3 mRN A molecules by the thousands then segregated a Remain dormant until fertilization 4 Morphogenetic Factors also segregated a Control differentiation of daughter cells 5 Protective Chemicals a UV ltering in protective coatings b DNA repair systems c Bird eggs even have antibodies d Chemicals that just plain taste bad b The Yolk is an Energy Storehouse 1 Proteins fats and glycogen packed in tight a Proteins also provide nitrogen source b Fats carry the most chemical energy per gram 4 Protective Coatings of Eggs a Cell Membrane 1 Primary osmotic and ionic lter 2 Helps to identify speciesspeci c sperm b Zona Pellucida or Vitelline Envelope 1 ZP is mammalian specialized extracellular matrix 2 VE is invertebrate protective layer c Cumulus 1 Also mammalian thick layers of follicular cells 2 Sperm have to get past them to reach the egg d Egg Jelly l Glycoproteins that attract and activate sperm 5 The Cortex a Cortical Granules act during fertilization to stop polysperrny b Actin Gel can polymerize for cytokinesis 6 Maturity Differs Among Species a Sperm Enters the Diploid Primary Oocyte l The roundworm Ascaris 2 Dogs and Foxes b Sperm Enters in the First Metaphase l Insects 2 Star sh c Sperm Enters in the Second Metaphase l Amphibians 2 Fish 3 Most Mammals d Sperm Enters After Meiosis l Cnidarians anemones 2 Sea Urchins 2 Mechanisms of Oogenesis a Polarity of the Egg Comes from the Anatomy of the Ovary l The cells around the egg are differentially distributed a Signals give animalvegetal polarity usually anteriorposterio 2 The nucleus germinal vesicle is asymmetric toward the animal pole a Also the direction that polar bodies are extruded 3 Associated with microtubular organization and RNA distribution 4 Vegetal pole is yolk accumulation portion of the egg b The Processes of Egg Maturation l The egg must acquire readiness for fertilization a Chromatin must fully condense b Membranes must adjust for a whole new physical environment c The egg must get ready to identify and fuse with sperm 2 The cell types and stages a Oogonia nish mitotic division prior to sexual maturity b Primary oocyte arrests in early prophase I c Follicular cells surround and support the oocyte d Pituitarygonadal cyclic hormones stimulate ovulation of egg e A second arrest occurs in most vertebrates at metaphase 11 f Fertilization stimulates progression of meiosis IV Fertilization The primary function of spermegg fusion is the passing of genetic material from both parents to the offspring A Recognition of Sperm and Egg 1 Sperm Attraction a Chemotaxis in external fertilizers 1 Can act over amazingly long distances b Coordinated attraction and movement in internal fertilizers l Capacitation is nal maturation 7 preparation for acrosome reaction 2 Allows sperm to pass the cumulus cell layer 2 The Acrosome Reaction a The vesicle membrane fuses with sperm plasmamembrane to release contents 1 In most external fertilizers contact with egg jelly cause reaction a Very speciesspeci c proteins in the jelly 2 In mammals it is the zona pellucida a the mammalian glycoprotein is called ZP3 b Proteolytic enzyme release results from calcium release upon binding and allows nal penetration to the egg membrane 1 External fertilizers breakdown the egg jelly 2 Intemal fertilizers breakdown the zona pellucida B Sperm Egg Fusion 1 Species Speci c Recognition in Sea Urchins a The acrosome reaction produces an actin driven extension of acrosomal membrane called the acrosomal process b The process is covered with speciesspeci c protein called bindin that binds to speci c receptors on the vitelline envelope c Binding reaction is the only mechanism by which the membranes can join 2 Gamete Binding and Recognition in Mammals a ZP3 is only relatively speciesspeci c for sperm binding to zona pellucida b It is exclusive for initiating the acrosome reaction however c Only speciesspeci c sperm get through the zona pellucida 3 Sperm and egg plasma membranes are able to fuse due to compatible lipid and protein signatures a Fusiogenic proteins Another critical check on speciesspecificity C Prevention of Polyspermy 1 Fast Block a Rapid change in membrane potential cause temporary block 1 The egg membrane goes from 70mV to 20mV in l3 seconds 2 Sperm can get in at 70mV but not at 20mV 2 Slow Block a The cortical reaction due to cortical granule release l The voltage change cause a calcium wave the causes fusion of granules with plasma membrane 2 Release of granular contents causes permanent block b In external fertilizers causes formation of fertilization envelope 1 hardening of vitelline envelope c In intemal fertilizers causes zona to become unreactive to sperm 1 Enzymes cleave ZP3 D Fusion of the Genetic Material 1 The male nucleus centriole and mitochondria get inside tail is lost 2 In sea urchins the female is already haploid male centriole immediately forms spindle to draw two pronuclei together 7 takes about an hour 3 In mammals female is in metaphase II 7 fusion has to wait a It waits so long that DNA is replicated separately and first division happens before they unite 7 first true diploid is in 2cell stage V Assymetric Division 0fthe Ovum Wow so we are going to talk about embryos after all As we ve seen he penetration of the egg by a sperm cell and its subsequent resistance to all others is very interesting What happens shortly afterward is why we re here Once the egg begins to respond to the presence of the sperm development of the organism begins The events that lead to the rst asymmetric division go far beyond the mixing of genes Many events are unrelated to the pronuclei Not surprisingly these ancient events are similar in different organisms Real differences between developmental strategies begin during the formation and development of blastula and gastrula stage embryos This section discusses and compares these early events in several species Finally we will look at the molecular mechanisms by which embryos establish their ups and downs and rights and lefts aka Axis Formation This is where it all begins A The Activation of Egg Metabolism p 203 1 The egg is divided into different domains to begin with a The animalvegetal axis and the animal vs vegetal hemispheres and poles b The cortical vs subcortical cytoplasms 2 Calcium waves increase cytosolic Ca ten fold in nearly all species a Chelating CaH stops development adding it without sperm can re up events b The successive waves produce successive events 1 Early Responses a Activation of membrane synthesis by active NAD kinase b Restoration of cell cycle through inactivation of cyclin etc 2 Late Responses a Stimulation of protein synthesis by interaction with high pH 1 Proteins from stored egg mRNA not sperm mRNA b Stimulation of DNA replication by MAP kinase inactivation c Movement of cytosolic components 3 Later events require a given number of waves a Maybe concentration maybe number of waves 3 Degradation of sperm mitochondria and their DNA occurs in the egg 1 DNA is protected from recombination mutation isn t diluted with male DNA 2 That s why we track historical species and migrations through mito DNA B Rearrangement of Egg Cytoplasm p 210 1 Not dramatically visible in all organisms but dyes will show that it occurs 2 The sperm can penetrate at any point around the circumference of the sphere a Entry causes rotation of the cortical cytoplasm 30 toward entry point b The rotation is caused by 39 L 39 39 arrays quot the r39 1 Interestingly arrays are composed of tubulin from sperm and egg 2 The centriole initiation site guiding them is from the sperm C The First Cell Division Follows Rearrangement 1 Calcium waves have started cell cycle activities 2 Cytosolic rearrangements have set up the essential asymmetry 3 The cleavage plane forms at the site of pronuclear fusion VI Cleavage and Blastula Formation In most organisms cleavage starts as a highly accelerated mitosis that divides the cytosol of the egg into many small cells based on the stored instructions in the maternal mRNA The developing cells then undergo a transition to expression of new mRNA s from the newly combined genome and differential development in the organism is truly off and running The blastula is the structurally organized cell mass that forms by these cell divisions and by uid secretion It is this structure that prepares the embryo for the rst migratory restructuring that comes with gastrulation Most animals are similar in their basic mechanisms of development at this stage and we ll talk about several using the bird as our primary model We will then talk about a group of animals that have developed some truly new strategies for these early stages the mammals 1 The Basic Mechanisms of Cleavage p 222 a Rapid Cell Divisions Lacking the Gap Phases of Mitosis Divide Up the Egg Cytosol 1 G1 and G2 are the times that cells grow in size prior to division 2 Cells only have time for S synthesis and M mitosis phases 3 The rate of nuclear multiplication is off the chart a Frog egg can divide into 37000 blastomeres in 43 hours b Drosophila forms 50000 cells in 12 hours 7 10 minute cell divisions 4 Most organisms have extremely synchronous cleavages and exponential growth b Cycling of the MitosisPromoting Factor Through Expression and Degradation of Cyclin l MPF Activity is High in Mphase and low in Sphase 2 MPF has two subunits 7 Cyclin B and CyclinDepenedent Kinase cdc2 3 Cyclin B is translated from maternal mRNA then the protein is degraded 4 When Cyclin B is Attached cdc2 Phosphorylates its Target Proteins a Phosphorylation of histones causes chromosome condensation b Phosphorylation of lamin causes breakdown of the nuclear envelope c Phosphorylation of myosin causes organization of the mitotic spindle c The MidBlastula Transition to Genomic mRNA Direction 1 Eventually the Stored Mitotic Regulators Run Out 2 Synthesis of mRNA from Combined DNA is Now Driven by Blastomere Position 3 G1 and G2 are reintroduced and cells start to grow during mitosis a Frogs reintroduce them both afterl2 cleavages b Drosophila reintroduces G2 after 14 G1 after 17 4 Synchronicity of Cell Divisions is Lost as Cells Make Different MPF Regulators d Patterns of Embryonic Cleavage 1 Pattern Depends Primarily on the Amount and Distribution of Yolk in the Egg a The vegetal pole is de ned as yolkrich the animal pole as yolkpoor b A ton of yolk makes cleavage occur in a disk shape at the animal pole 2 Different Inherited Patterns of Cell Division Can Also Affect the Cleavage Pattern a Most obvious in yolkpoor eggs e Speci cation of Cell Fates During Cleavage 1 Due to Assymetric Distribution of Patterning Molecules During Cleavage a Passive acquisition due to location of cytoskeletal attachment b Active transport to predetermined cells c Organized association with a single centriole 2 The Chickens Now Representing Birds Fish and Reptiles p 354 a Meroblastic Discoidal Cleavage 1 Initial cell divisions are all meridional and highly synchronous 2 All cells start out continuous with the yolk at their base b Formation and Development of the Blastoderm l Equatorial vertical divisions then form multiple layers of cells 2 Most cells lose their continuity with the yolk by physical separation c Dissociation of the Blastoderm from the yolk 1 Cells of the blastoderm absorb water from the albumin and secrete it again d Formation of the TwoLayered Blastula l The epiblast contains all of the embryo cell fates a Apoptosis in the inner cells of the blastoderm leave a single layer b A ring of multiple layers is maintained at edge 7 the marginal zone 2 The hypoblast contains most of the nonembryo cell fates a Formed by combination of marginal zone cells delaminating epiblast 3 The Mice Now Representing all of Mammalia p 363 a Holoblastic Rotational Cleavage 1 Like most things mammalian these are the last things we learn about a Very dif cult to study b The human egg is less than 11000 the volume of xenopus eggs 1 100 pm in diameter 7 barely visible to the human eye c Produced in much smaller numbers and far less accessible d Egg is encased in the zona pellucida extracellular matrix shell 1 Keeps it from implanting in the fallopian tubes 2 Extremely slow cleavage 7 probably related to delayed traverse down the tubes a 1224 hours apart b Start in the oviduct b Very different cleavage pattern 1 First cleavage is normal meridional 2 Second is half meridional and half equatorial 3 Cleavages are asynchronous a Often contain odd numbers of cells during development 4 Cells start out loose and then undergo compaction a Express tight junctions and gap junctions c Mammalian combined genome is active much earlier than most organisms l The switch from maternal mRNA s occurs at twocell stage in mice and goats 20 d Formation of the morula at about the l6cell stage 1 Cells become either inner cell mass or trophoblast a Inner cell mass cells have all embryo fates b Trophoblasts have nonembryo placental fates c Can divide into one or the other until 64cell stage then are committed 2 First fullblown differentiation in the mammalian embryo e Cavitation and Blastocyst Formation l Trophoblasts pump sodium in to the morula central cavity water follows 2 The water filled cavity is called a blastocoel and the embryo a blastocyst f Escape from the Zona Pellucida and Implantaion in the Uterus l The blastocyst secretes proteases and cuts a whole it can squeeze through 2 The blastocyst then cuts a whole and settles into the lining of the uterus 21


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