Migration of Neurons During Embryonic Development. Christine Simmons Saint Louis University April 15 th, 2008

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1 Migration of Neurons During Embryonic Development Christine Simmons Saint Louis University April 15 th, 2008

2 Embryonic Development of the CNS Central Nervous System (CNS) arises from Surface ectoderm Skin, hair and Neural ectoderm Neural tube Neural crest cells Cranial, cardiac, trunk and vagal/sacral

3 Embryonic Development of the CNS The neural tube is a straight structure Neural tube expands to form three primary vesicles and their secondary structures Prosencephalon Telencephalon Diencephalon Mesenecphalon Rhombencephalon Metencephaoln Myelencephalon Neuroscience figure 22.5

4 How does a single layered epithelial give rise to the multi-layered, complex CNS? Neuronal Precursor Cell Cycle Neuronal precursor cell cycle Rapid mitotic division increases number of cells Structural and systematic arrangement Cells contact both luminal and outer surface M phase might be an exception During S phase the nucleus migrates to the outer surface and then returns to the luminal surface Daughter cells of a single precursor vertically align When cells are ready to differentiate, the plane of division changes One cell stays in the neuroepithelium One cell migrates and differentiates (birthday)

5 Neuronal Precursor Cell Cycle Neuroscience figure 22.7

6 Tissue Architecture of the Neural Tube Migration of cells with relationship to birthday Earlier birthdays migrate the shortest distance Later birthdays migrate longer distances (superficial layers) Migration of cells leads to a second layer called the intermediate zone The neuroepithelium is now called the ventricular zone Differentiation in the intermediate zone Both neurons and glia differentiate Axons of neurons extend away from the lumen and form a marginal zone The tissue architecture of the neural tube gives rise to: Spinal cord Cerebrum Cerebellum Developmental Biology figure 12.16

7 Tissue Architecture: Spinal Cord The architecture of the neural tube gives rise to architecture of the spinal cord (and medulla) Intermediate zone is gray matter Marginal zone is white matter Developmental Biology figure 12.16

8 Tissue Architecture: Cerebellum The architecture of the neural tube gives rise to the architecture of the cerebellum Neuroblast migration External granule cell layer Granule cell layer Developmental Biology figure 12.16

9 Cell Types in the Cerebellum Granule neurons Bergman glial cells Purkinje neurons Developmental Biology figure 12.18

10 Tissue Architecture: Cerebrum The architecture of the neural tube gives rise to the architecture of the cerebrum Developmental Biology figure 12.16

11 Neuronal Differentiation Neurons become differentiated once they reach their final or correct position Neuronal differentiation is dependent upon: Intrinsic cues Proteins expressed by the migrating neuron Receptors ECM proteins Extrinsic cues Paracrine signaling molecules Proteins secreted by glial cells Microenvironment Timing Last cell division

12 How do neurons get to their correct position? Neuronal Migration Two routes of neuronal migration Radial route Construct laminar cyto-architectures Two distinct sub-types Translocation» Long leading process attached to pial surface» Shortening of the process and pulling of the soma Locomotion» Leading process maintains length and does not attach to the pial surface (neuronal crowd surfing) Tangentially Gliding across the glial fiber system

13 How do neurons get to their correct position? Neuronal Migration Two routes of neuronal migration Radial route Construct laminar cyto-architectures Two distinct sub-types Translocation» Long leading process attached to pial surface» Shortening of the process and pulling of the soma Locomotion» Leading process maintains length and does not attach to the pial surface (neuronal crowd surfing) Tangentially Gliding across the glial fiber system Ghashghaei, Lai and Anton. Nature Reviews :141

14 Radial Migration Molecules Key molecule on the glial fiber αv integrin, laminin, fibronectin, NGCAM1 Key molecule at glial endfoot Reelin Key molecules on the migrating neuron Neuregulin, Lis1, astrotactin, DCX Neuroscience figure 22.12

15 What are the molecular mechanisms regulating neuronal migration? Molecular Cues Mechanisms underlying cell migration are complex Regulated by 100s of different genes and their products Dependent upon microenvironment Extracellular guidance cues are interpreted through receptors that relay signals to various networks of signaling cascades Converge onto the cytoskeletal system Actin (microfilaments) Myosin and tubulin (microtubules) Many of the molecules involved in neuronal migration are also involved in axonal growth, axonal guidance and synapse formation

16 Ayala et al. Cell

17 Historical Insights from Mutant Mice Autosomal recessive mutation, unsteady gait phenotype Mutant do not make the protein Reelin Results in incorrect placement of neurons Correlated with inappropriate neuronal migration Neuroscience Box 19B Figure A Developmental Biology figure 12.18

18 Current Research on Molecules Associated with Neuronal Migration Reelin Reelin is a secreted extracellular matrix glycoprotein Receptors are LDLR Family VLDLR ApoER2 Reelin receptors may play a role in Alzheimer s disease Herz and Chen. Nature Reviews :850

19 Current Research on Molecules Associated with Neuronal Migration Netrin Recptor DCC Netrin functions as an environmental cue for migration Chemo-attractant or in repulsion Conserved in eukarya Structurally similar to laminin Netrin receptor is DCC (Directed in Colon Cancer) Receptor on migrating cell Ig Superfamily of receptors

20 Current Research on Molecules Associated with Neuronal Migration Slit and Roundabout (Robo) Slit is a chemo-repellant molecule Secreted by glial cells at the midline Robo (roundabout) is a receptor Originally identified in Drosophila Seeger 1993 identified based on mutants whose axons cross the midline repeatedly Ig domains Fibronectin domains Dickson and Gilestro. Annu. Rev. Cell Dev. Biol :651 75

21 Current Research on Molecules Associated with Neuronal Migration Semaphorins Semaphorin is a gene family identified in Drosophila Membrane bound TM domain, sema domain Secreted Ig domain, sema domain Binds to a neuropilin receptor Involved in forming right angle turns in axonal guidance

22 Current Research on Molecules Associated with Neuronal Migration Microtubule Associated Proteins Lis1 Mutants lead to lissencephaly Interactions with dynein and other MTOC proteins Lis1-dynein inhibited in Drosophila oogenesis DCX DCX mutants affect velocity of migration, nuclear translocation and branching of leading process Does not affect direction X-linked lissencephaly Females have subcortical band hetertropia (MAPs) Feng and Walsh. Nature Reviews :408

23 Current Research on Molecules Associated with Neuronal Migration Astrotactin Glycoprotein associated with migrating neurons Allows the neuron to contact radial glial cells Follow the frame-work for migration

24 Review of Neuronal Migration Migratory Initiation Events Intrinsic cues Robo Dcc Extrinsic cues Netrin Slit Maintenance of Migration Intrinsic cues Integrins ErbB4 Extrinsic cues Neuregulin Migratory Termination Events Intrinsic cues ApoER2 Extrinsic cues Reelin Ghashghaei, Lai and Anton. Nature Reviews :141

25 Why are these molecular cues important? Diseases Associated with Neuronal Migration Defects Neuronal migration is vulnerable to mutations that disrupt: The ability of the neuron to move The ability of glial cells to support migration Both neuron movement and glial support Diseases include: Lissencephaly Polymicrogyria

26 Lissencephaly Commonly called smooth brain Normal brains have convolutions and folds These are missing or partly-developed in lissencepahly Diagnosed via MRI Abnormal cortical layering and cytoarchitecture Enlarged ventricles Many disorders fall into the category of lissenecephaly Some due to viral infection in first trimester, insufficient blood supply and also genetics (DCX gene) Symptoms include Mental retardation Inconsistent visual tracking Seizures Life expectancy Typically <20 years Feng and Walsh. Nature Reviews :408 Piao et al. Science :2033

27 Beyond Neuronal Migration Molecular toolbox Same genes used throughout the body to achieve similar functions Cell adhesion/ migration molecules are also involved in: Epithelial pattern formation Axonal guidance» Possible therapeutic values in regeneration Synaptic formation

28 References Dickson, B. J. and G. F. Gilestro (2006). "Regulation of commissural axon pathfinding by slit and its Robo receptors." Annu Rev Cell Dev Biol 22: Feng, Y. and C. A. Walsh (2001). "Protein-protein interactions, cytoskeletal regulation and neuronal migration." Nat Rev Neurosci 2(6): Fishell, G. and M. E. Hatten (1991). "Astrotactin provides a receptor system for CNS neuronal migration." Development 113(3): Ghashghaei, H. T., C. Lai, et al. (2007). "Neuronal migration in the adult brain: are we there yet?" Nat Rev Neurosci 8(2): Gilbert, S. F. (2006). Developmental Biology, Sinauer Associates. Herz, J. and Y. Chen (2006). "Reelin, lipoprotein receptors and synaptic plasticity." Nat Rev Neurosci 7(11): Hinck, L. (2004). "The versatile roles of "axon guidance" cues in tissue morphogenesis." Dev Cell 7(6): Kawauchi, T. and M. Hoshino (2008). "Molecular pathways regulating cytoskeletal organization and morphological changes in migrating neurons." Dev Neurosci 30(1-3): Mann, F., S. Chauvet, et al. (2007). "Semaphorins in development and adult brain: Implication for neurological diseases." Prog Neurobiol 82(2): Marin, O. and J. L. Rubenstein (2003). "Cell migration in the forebrain." Annu Rev Neurosci 26: Nadarajah, B., J. E. Brunstrom, et al. (2001). "Two modes of radial migration in early development of the cerebral cortex." Nat Neurosci 4(2): Pellet-Many, C., P. Frankel, et al. (2008). "Neuropilins: structure, function and role in disease." Biochem J 411(2): Piao, X., R. S. Hill, et al. (2004). "G protein-coupled receptor-dependent development of human frontal cortex." Science 303(5666): Purves, D. e. a. (2008). Neuroscience, Sinauer Associates. Zhou, Y., R. A. Gunput, et al. (2008). "Semaphorin signaling: progress made and promises ahead." Trends Biochem Sci 33(4):