VOKES DEVELOPMENTAL BIO EXAM 2 STUDY GUIDE
VOKES DEVELOPMENTAL BIO EXAM 2 STUDY GUIDE BIO 349
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This 4 page Study Guide was uploaded by Clayton Payne on Thursday March 3, 2016. The Study Guide belongs to BIO 349 at University of Texas at Austin taught by Dr. Steven Vokes in Spring 2016. Since its upload, it has received 34 views. For similar materials see Developmental Biology in Biology at University of Texas at Austin.
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Date Created: 03/03/16
VOKES EXAM 2 STUDY GUIDE Somitogenesis and Muscle Formation ● Somites are formed from paraxial (presomitic) mesoderm ● Generation of oscillating Notch activity ○ ● Generation of somite boundaries ○ The border of a new somite is specified by activated notch, as demonstrated by an experiment where a strip of nonboundary mesoderm cells from one embryo were electroporated with Notch and then transplanted to another embryo ● Limb Development ● Specification of limb bud location ○ Specific Hox gene expression induces migration of lateral plate mesoderm consistent across species ● Fore/hindlimb specification ○ In limb fields, Hox proteins activate retinoic acid synthesis, which induces expression of Tbx proteins in the lateral plate mesoderm, and in the limbs. Tbx5 specifies forelimb, Tbx4, and possibly one of its downstream targets, Pitx1 specifies hindlimb. ○ Certain breeds of pigeon with feathery feet show expression of both Tbx5 and Tbx4 in their hindlimbs more feathery = more Tbx 5, as well as less Pitx1 Tbx5 is making the hindlimb more forelimblike. Tbx5 and Pitx1 are possibly mutated in fancy pigeon breeds, possibly in the enhancer region (like with sticklebacks) ○ Mice are a different story Tbx4/5 are necessary to form forelimb/hindlimb (Tbx5/ have no forelimb), but not sufficient. According to the textbook, Forced expression is not sufficient to transform forelimb to hindlimb, but Pitx1 is. Still debated. ● Early limb bud outgrowth ○ Fgf10 is sufficient and necessary to activate limb bud outgrowth WT Tbx with / Fgf10 have no limbs ○ Tbx4/5 (trxn factors) both activate Fgf10, a secreted growth factor, in the lateral plate mesoderm. ○ Fgf 10 is secreted, activating Wnt3 in the apical ectodermal ridge. AER is an ectoderm extension at the border of dorsal and ventral limb ectoderm. ○ Wnt3 activates Fgf8 Wnt3 mutants have no limbs ○ Fgf8 is secreted back onto the mesoderm, activating more Fgf10. This positive feedback loop is necessary to maintain outgrowth ○ Fgf4 is closely related to Fgf8 and can cove for Fgf8 / ○ Msx (limbspecific) Cre knockout for Fgf4/8 are imperfect ■ Forelimb begins growing before hindlimb ■ Forelimb will begin to grow before Cre becomes active ○ Thalidomide causes limbloss phenotypes ■ Thalidomide produces appr. 60 metabolites ■ Progressively later treatment with Cps49 causes progressively more limb outgrowth before it halts. Seems to inhibit limb vascularization ● Migration of mesenchymal mesoderm cells ○ Lateral plate mesoderm gives rise to skeleton ○ Muscle progenitors from somite myotome migrate in after limb bud has already formed ○ AER prevents mesenchyme directly beneath it from forming cartilage as limb grows ● ProximalDistal axis polarity ○ Polarity (what structure forms at what position) is determined by the differentiating (proximal) mesenchyme. Transplanting a new AER/proximal mesenchyme onto an old limb bud causes repeat structures to form. ○ Specifically, it is determined by the gradient of Wnt/FGF which starts distally, and the gradient of retinoic acid which starts proximally. Repack ectoderm w/ mesoderm treated w/ Fgf+Wnt > more distal limb structures form; You see Hoxa11/13 more proximally, and Meis1 less distally. ○ Fgf8 inhibits mesenchyme from forming skeletal cartilage ● AnteriorPosterior polarity ○ The zone of polarizing activity (ZPA) is a posterior Shhsecreting structure. ○ ZPA is specified shortly before limb bud becomes visible ○ A transcription factor inhibits the limbspecific Shh enhancer from being active in the anterior limb bud. A certain mutation in this enhancer region results in polydactyly, due to inability of repressor to bind. ○ Expressing Shh anteriorly results in extra digits; transplanting a ZPA to the anterior (two ZPAs) results in a mirror hand ○ Digit identity is determined by: 1) Shh concentration and 2) Length of exposure of Shh ● Later outgrowth ○ When ZPA is first established, Shh activates Gremlin in the mesoderm. Gremlin activates FGF interactions ○ Positive feedback causes Fgf levels to rise, until they pass a threshold where they begins to repress Gremlin, creating a zone in the distal mesenchyme that does not secrete Gremlin. ○ As this zone proliferates, less Gremlin can reach the AER, causing FGF levels to drop, and the positive feedback loop driving outgrowth to disintegrate. When FGF levels are low enough, embryonic limb growth ceases. ● Bone formation ○ Apoptosis between digit regions (and at joints) allows fingers, toes, and other digits to form normally ○ BMPs can induce mesenchymal cells to become chondrocytes (cartilage cells) or apoptose depending on the molecular context ○ Sox9 is a master regulatory transcription factor for chondrocytes. Sox9 heterozygotes develop with bowed and bent long bones. ○ Discrete condensate nodules may form via a Turing mechanism, in which signals diffusing at different rates mutually repress one another. Evidence? When Wnt, Sox9, and BMP levels from anterior to posterior in a limb bud stabilize, Wnt and Sox9 levels peak out of phase from each other, suggesting mutual repression. ● From condensates to bone ○ First, nodules begin to condense via mechanisms involving celladhesion molecules. Outer cells will become osteoblasts (bone cells), inner cells will become chondrocytes. ○ Second, chondrocytes proliferate. ○ Third, chondrocytes at the center of the condensate become hypertrophic, secreting Ihh and VegF. VegF will attract blood vessels. Secreted Ihh will induce osteoblasts surrounding the hypertrophic center. (Ihh mutants = no osteoblasts) Secreted Ihh will also stimulate PTHrP production at the proliferation front, producing a wavefront of PTHrP from distal to proximal. Hypertrophic chondrocytes also induce the extracellular matrix to become mineralized, forming a cartilage scaffold ○ PTHrP in turn represses Ihh production, which keeps chondrocytes proliferating at the secondary ossification center. In this way, Ihh, PTHrP interactions prevent premature differentiation of chondrocytes/loss of limb length. PTHrP mutations produce dwarfism. ○ The PTHrP production may come first, with the Ihh interaction following. ○ As the wavefront moves forward with growth, more chondrocytes become hypertrophic. ○ Hypertrophic cells eventually apoptose, allowing osteoblasts and blood vessels to invade the cartilage scaffold. ○ FGFs inhibit chondrocyte proliferation. Shortlimbed dogs have a retrogene insertion of FGF4. The elevated FGF causes premature differentiation of chondrocytes. ○ A mutation in one allele of FGF receptors will cause achondroplasia, the most common form of dwarfism.
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