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Bio 599- Neural Migration II & III

by: Molly Burdsall

Bio 599- Neural Migration II & III Bio 599

Marketplace > University of South Carolina - Columbia > Biology > Bio 599 > Bio 599 Neural Migration II III
Molly Burdsall


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About this Document

These notes cover our 2nd and 3rd lecture over Neuronal migration.
Cellular and Molecular Biology
Dr. Fabienne Poulain
Class Notes
Biology, Neural Migration, Molecular, neuroscience
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This 9 page Class Notes was uploaded by Molly Burdsall on Thursday February 18, 2016. The Class Notes belongs to Bio 599 at University of South Carolina - Columbia taught by Dr. Fabienne Poulain in Winter 2016. Since its upload, it has received 6 views. For similar materials see Cellular and Molecular Biology in Biology at University of South Carolina - Columbia.


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Date Created: 02/18/16
16 February Review  dynamic microtubules work with actin bundles  several actin proteins regulate polarization and depolarization  Family of Rho GPA regulate the cdc42  Cdk5- very important inguding Rhoa and Rac1 and  Dynein very important in mechanism of centrosome Part II: Neuronal migration in the cerebral cortex  Reminder: excitatory gltamertgic neurons (oriinate from progenitors in ventricular zone) and inhibitory neurons that populate the cortex from the outside and migrate tangentially to populate the cortex  6 different layers to cortex: progenitors I the ventricular and subventricule zone and produce progenitors and neurons which migrate o progenitor split into neurons and do radial migration  Somal translocation as the first mode of radial migration at early stages o Video displays that the cell body translocates and brings cell body up into upper layer  Glial-guided locomotion as a later mode of neuronal migration o Neurons that are formed use radial glaila process to migrate o Researchers: inject modified virus into the cortex and cut the brain into slices--- videomicroscopy of slices—neurons migrate along radial glial process o CONTACT BETWEEN NEURONS AND RADIAL GLAIAL FOR MIGRATION IS VERY IMPORTANT  Glial-guided locomotion requires tight contacts between enruons and radial glia o Lead process of neuron-migrating neurons- o Molecules?: Integrins  Integrins mediate adhesion between neurons and radial glia o Experiment: reproduce mode of transportation in neuron with micro glial and neuron (control)  Addition of a3 integrin ibhibitor- Inhibitor placed after time one and completely blocks the migration of the neuron o Experiment: addition of a5 integrin ibhibitor- neurons do not even come intact with radial glial  Integrins are transmembrane heterodimeric receptors linked to actin o Arp2/3 complex: proteins that make protein network o Integrins connected to cytoskeleton and produces traction  Integrins mediate adhesion and migration o Proteins (with integrin) connected to actin cytoskeleton o Force of myosin II forces movement o PROVIDE THE TRACTION FOR MOVEMENT  Gap junctions and radial migration o Connexins are required for radial migration  Experiment: modified DNA injection at E16  Control: migration of neurons at E21  Cx 26 mutation (neurons don’t go as far- less migrate)  Cx43 mutation (???) o Connexins form GAP junctions between cells  This sytem mediates two things  1. Adhesion between two cells (binding stimulates adhesion)  2. Channel to transports molecules from one cell to another  connexon is formed by 6 connexsins o connexins are at contact points between neurons and glia o The adhesion property of connexins is important for neuronal migration  C-terminus: binds to other proteins and mediates transmission pathways (specific interaction)  Adhesion:  Channel: Experiment:  Connexin-43 mutant mouse  1. Inject DNA injection at E16: GFP + connexin-43 domains  In theory you should restore migration in mutatnt mouse  Control: neurons migrate from ventrizclar zone to CP  Mutant mouse: migration does not happen- neurons in VZ  With connexin-43 domain: neurons do as they should-migrate to CP  Connexin-43 domains to only channel and c-terminus but NO adhesion domain: neurons do not migrate  Connext-43 domain to adhesion, c-terminus NO channel: neurons migrate as normal  Connexin-43 domain to adhesion NO c-term or channel: restores migration-normal migration  WHAT CAN WE CONCLUDE: ADHESION IS NEEDED FOR NORMAL MIGRATION  Cues regulating radial migration o Where to stop? o The discovery of the Reeler mouse- ataxia, tremor, reeling gait  The 6 layers are not distinguished in Reeler mouse— division of cortical layers is completely disrupted.  Abnormal layers in the Reeler mouse  Neurons are disorganized and almost reverse o Neurons are produced but migration is completely disrupted—cannot form the proper upper layers because it is disrupted o Reeling is a large secreted glycoprotein  Reelin is detected in the marginal zone containing Cajal-Retzuis cells  Red (reelin) is in marginal zone of cortex  Special population of cells in upper region of cortex: cajal-retzius cells at marginal zone of cortex  Reelin binds to VLDLR and ApoER2 receptors  VLDLR: Very low density lipoprotein receptor  ApoER2: apolipoprotein E Receptor 2  Effect of VLDLR and ApoER2 mutations  Early-born neurons o Wild-type o Reeler mutatnt o VLDLR+ ApoER2 mutatnt: same effect as Reeler mutant  Late neurons o Wild-type o Reeler mutatnt o V & A mutatnt: same effect as Reeler mutant  Studying V and A independently o VLDLR mutatnt: neurons migrate TOO far in early and late migration No “stop” signal o ApoER2 mutant: early (migrate too far up) late (don’t migrate at all) No “go” signal  Dual function of Reelin: migration and arrest o Reelin signaling to migration neurons  The Reelin/Dab-1 transduction pathway  Neurons that express VLDLR and ApoER2  Reelin arrives and binds to two receptors  Leads to the activation of SFKs kineins  Regulate (3) Dab-1 proteins (main regulator of Reelin)  Dab-1 activates the chineses P13K  P13K activates Rac 1 & Cdc42—inhibits GSK3B o Rac 1 & Cdc42- regulate actin o Rac 1 & Cdc42 modlules the polarization of actin polymerization and turnover o Inhibited GSK3B allows microtubule stabilization through APC  One Dab-1 modulates Lis1 which allowd dynein and APC  *** Lis1 can interacte with VLDLR but not ApoER2??  Other guidance cues involved o Semaphoring-3A guides radial migration  Attracts or repels cells since it is a guidance cue  Migration impaired if sema-3A is blocked  Defect in migration if neuropilin-1 is blocked Review  Later stages the neurons travel up radial glial  Section of Reelin (cajal-Rezius cells) o Binds to VLDLR and ApoEr2  Tells Neuron migration (promotes and where to stop) and arrest  Secretion of Sema-3A o Binds to Nrp1 and Plexin  Promotes neuron migration and direction  Contact of neurons and radial glaial is very important o 2 proteins that mediate the contact  1. Integrins  2. Connexins  adhesion between neurons and radial glia, migration Case Study: Lissencephaly  Lissencephaly: smooth brain, absence of folds and grooves  Psychomotor retardation, seizures and epilepsy, failure to thrive, muscles spasticity, hypotonia, shorter life expectancy o Estimate 1/100,000 newborns  Lissencephaly is caused by defects in neuronal migration  Mutations found in these patients: o Depending on mutation there is a different class that differentiates slightly  Mutation in Reelin--  Mutation in Lis 1 (named after the disease)--  TubA1a--  Dcx (double cortin)—mictrobules stabilization Feb. 18 Review  Connexins make connexons which allow gap junction Tangential migration of interneurons  Lateral geniculate emulance  Medial geniculate emulance—neurnos mainly come from this site o Migrate transjunctinoally o Dynamic neurons- switch direction o Not guided by glial process- find their way in the environment of the cortex  Steps of Neuron migration o 1. Excit from the proliferative zone in the mediagl ganglionic eminence (and POa), initiation of migration o 2. Selection of migratory route towards the cortex (pass LGE to find entry of the cortex) o 3. Choice of migratory stream within the cortex o 4. Local orientation of migration within the cortical wall o 5. Identification of final laminar location o 6. Termination of migration at the appropriate layer  How do they exit the MGE? (step 1) o Ephrin-A5 is a chemotaxis cues localized in the MGE  Ephrin-A5 repels interneurons  Experiment: o Dissociation of neurons  Culture: stripe assay (dark lines are control; light lines are ephrine-A5)  Neurons tend to avoid ephrin- A%-Fc stripes and go towards control stripes o The family of Ephrins and their Eph receptors  Two categories  1. Ephrin-A (encode at cell phase- no intracellular domain)  2. Ephrin-B (intracellular domain! have two domains??) o Both bind to Eph receptor (Eph-B and Eph-A receptor)  Forward signaling: from ephrin to Eph  Reverse signaling: from Eph to ephrin o Ephrin-A5 repels interneurons expressing EphA4  Ephrine-A5 produced in MGE which repels all of the neurons  How do the migrate along the LGE and Str (Step 2) o The role of neurotropic and growth factors  Family made up of four members  1. NGF  2. NT4, BDNF  3. NT3  4. NGF, BDNF, NT3, NT4  GDNF (very important) Not part of the same family since it doesn’t have the same receptor (not same category of molecule) but still a growth factor that has similar functions to the family  Neurotropic factors are motogenic factors (doesn’t give direction- just tells cells to move)  Experiement: o Culture of explants (addition of factors)  Control: All neurons leaving MGE  Add BDNG:  Add NT4:  Experiment: o Addition of beads coated with factors implanted near LGF  Control: BSA-coasted bead: neurons stay away from bead  GDNF-coasted beads: neurons surround bead  In RET mutant: neurons around bead  In GRFa1 mutant: not as many neurons around the bead  Conclusion about experiment: o 1. GDNF contributes to interneurons migration o 2. GFRa1 allows neurons to respond to GDNF Migration of interneurons to the cortex slide- REVIEW OF WHAT WE LEARNED—Ephrin-A5--- Neurotrophic factors: GDNF, BDNF, NT-4  Review of Striatum  Role of Striatum in the interneuron migration o Reward, planning of movement Neurons avoid the Striatum (step 3) o Experiment:  Transplant ectopic piece of striatum o Semaphorin-3A and -3f are present in the striatum o Experiment: *interneurons shown in red-Dil  Implant cells (not even brain cells-just cell) at the entry of the cortex (on each entry-2 sides)  Control: produce Gfp  Engineering the cell to produce Sema3A, Sema 3F, Gfp o Interneurons avoid Sema3A & Sema3F- repels interneurons o Semaphorins are big families  2 receptors: Neuropilins & Plexins o Experiment:  Control: avoid striatum  Neuropilin-2 mutant: cover the whole area  Neuropilin (receptor of Sema-3A) is absolutely required in order to have neurons repel against the region o Semaphorins are responsible for sorting MGE interneurons to their final destination  Interneurons to the cortex:  Express NRp-1 and Nrp-2  Repelled by striatal Sema-3s  Interneurons to the striatum:  Do NOT have nrp-1 and Nrp-2  Do NOT have…  Neuregulin-1 (Nrg1): one gene, different isoforms o Type 1 (Ig) o Type 2 (Ig) o Type 3 (CRD)  Nrg1-Ig is detected near the cortex (step 4??) o Receptor: ErbB4- present at the face of interneurons  Hypothesis: Nrg1-Ig is a magnet for neurons- attracts migrating MGE interneurons o Experiment: NrG1-Ig + Gfp into COS cells  Neurons are drawn to this area o Experiment: Interneurons lacking ErbB4 lose directionality  Control: neurons move towards cortex  ErbB4 mutatnt: neurons still move but loose their direction  Most interneurons migrate through the MZ and SVZ (few migrate to upper part of SP) o The chemokine Cxcl12 (Sdf-1) is produced by the meninges and the intermediate progenitors o Cxcl12 attracts interneurons migrating in the cortex  Cxcr4 and Cxcr7 receptors  Experiment:  Control: neurons go to appropriate places and migrate  Lack Cxcr4 and/or cxcr7: populate the cortex but do not find their way along the strings- pattern of migration is impaired  Colonization of the cortical plate o Interneurons colonize the cortex in an inside-out manner  Experiment:  Early brdu injection: populate lower layer of the cortex  Late BrdU injection: populate upper layer of the cortex o Interneurons lose their responsiveness to Cxcl12 over time (desensitization) *hang out here for awhile and then become desensitized so they stop migrating tangential and start migrating radially— me typing  Interneurons switch from tangential to radial migration and migrate along radial glia (to populate different layers of the cortex) o Pyramidal neurons determine interneuron final destination  Control:  Migration of pyramidal neurons ibhibited  By affecting pyramidal neurons you also effect the signal sent by pyramidal neurons which affects the migration of interneurons  Neurons stay in I, IZ, SVZ layers because they responde to Clcx12 o Loose response to Clcx12 and switch to radial migration instead of tangital migration  Populate different layers of the cortex (pyramidal cells give a signal to neurons of where to stop)


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