Chapter 11: Neural Crest Cell and Axonal Speciticity

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Chapter 11: Neural Crest Cell and Axonal Speciticity
2014-04-16 17:09:30

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  1. Neural crest cells are often called as the 4th germ layer
    Neural crest cells and axon growth cones migrate far from their source of origin to specific places in the embryo.

    • NCC originate at dorsal most region of neural tube
    • Recognize cues --> migrate --> respond to local signals --> differentiate
  2. Neural Crest Cell Migration
    Neural crest is a transient structure dorsal to neural tube.

    Neural crest cells (NCC) undergo epithelial-mesenchyme transition and start migrating.

    NCC have the ability to self-renewal (stem cell-like property)
  3. Origin and Specification of NCC
    Specification of NCC from neural plate boundary is a multi-step process.

    Neural Plate border specifiers (BMPs, Wnts and FGFs) --> induce expression of Neural Crest specifiers.

    Neural crest cells generate many cell types Fate depends on where they migrate to and settle
  4. Specificationof NCC
  5. Types of Neural Crest Cells
    Four Major functional domains of NCC

    •Cranial (cephalic) neural crest cells – produce craniofacial mesenchyme (cartilage and bone tissue of face)

    • •Trunk neural crest cells
    •     oPigment synthesizing melanocytes
    •     oDorsal root ganglia forming cells

    • •Vagal and Sacral neural crest cells
    •     oGenerate parasympathetic ganglia of gut

    •Cardiac neural crest cellsoDevelop musculo-connective tissue of the walls of large arteries and septa
  6. Trunk NCC – Migratory Pathways
    Ventral pathway --> form sensory and sympathetic neurons, adrenomedullary cells and Schwann cells

    Dorsolateral pathway --> travel through dermis --> colonize skin and hair follicles --> produce melanin (mealnocytes)
  7. Emigration of T-NCC
    • Presumptive ectoderm produces BMP 4 and 7 --> expression of Slug protein and RhoB protein in the cells destined to become neural crest --> start migration 
    •      Slug protein --> dissociation of E-cadherin  
    •      Rho B –promotes migration
  8. Mechanism of Trunk NCC migration
    Recognition of extracellular matrix - Path of migration is controlled by extracellular matrices 

    Migration promoting proteins – fibronectin, laminin, tenascin, collagens, proteoglycans  Thrombospondin, an ECM protein found only in the anterior side , promotes NCC migration

    Migration impeding proteins – Ephrin proteins, Semaphorin-3F
  9. NCC Migration – Recognition of ECM

    Chick NCCs express a4b1 integrin --> help in locomotion of NCC [NCC without a4b1 integrin --> disorientation --> apoptosis]

    Thrombospondin – found only in the anterior portion of sclerotome of somites --> promotes NCC migration
  10. Ephrins and T-NCC Migration
    Ephrin proteins are responsible for positioning of dorsal root ganglia --> segmentation, patterning of peripheral nervous system

    Ephrin proteins – expressed in the posterior side of the sclerotome.

    Neural crest cells express Eph receptors.

    Eph binding with its receptor interferes with migration.
  11. Dorsally Migrating T-NCC
    These NCCs remain in neural tube till the dermis is formed by dermotome.

    In contrast to ventral pathway, Ephrin stimulates the migration of NCC in dorsal pathway

    Dorso-laterally migrating NCC --> melanocytes

    Ultimately settle in the hair follicle bulge and become Melanocyte stem cells --> provide pigment to the hair shaft

         •Depletion of these stem cells à gray hair
  12. Pluripotency of T-NCC
    •Trunk neural crest cells can differentiate into many cell types

    •     oNeck region – they form parasympathetic (cholinergic) neurons
    •     oThoracic region – they form sympathetic (adrenergic) neurons

        oIf exchanged (transplanted) --> can form position specific neurons
  13. T-NCC differentiation
    Final differentiation is determined by local environment

    oBMP2 (secreted by heart, lung) --> cholinergic neurons

    oGlial growth factor --> glial cells

    oGlucocorticoids (in adrenal) --> adrenomedullary cells
  14. Cranial Neural crest cells
    • “Face” – initially is the art-work of Cranial neural crest cells

    Hind brain is segmented by Rhombomeres

    Cranial NCC follow 3 major pathways

    1st pathway – cells from r1 and r2 --> form jawbones, incus and malleus and fronto-nasal process

    2nd pathway – cells from r4 --> hyoid cartilage of neck and Stapes

    3rd pathway – cells from r6 --> Thymus, Thyroid and Parathyroid
  15. Cardiac Neural Crest Cells
    •Located between Cranial and Trunk NCC

    •Cardiac NCCs produce entire musculo-connective tissues of large arteries (Kirby et al. 2000)

        •Heart actually comes from lateral plate mesoderm

    In mice – Ca NCCs express Pax3

    •Mutations in Pax3 (Conway et al. 2002)

       •persistent truncus arteriosus (failure to separate aortas and pulmonary artery)

       •defects in thymus, thyroid and parathyroid glands
  16. Neuronal Specification
    •Specification of type of neurons is determined by position

       •Dorsal side --> sensory neurons (induced by BMPs)

       •Ventro-lateral margin of neural tube --> motor neurons (induced by Shh)
  17. Target Specificity
    •Target specificity is determined by birthday of neurons and mediated by Lim genes (structurally related to Hox genes)

    •Younger motor neurons --> migrate to periphery compared to older motor neurons
  18. Axonal Specification
    Function of Nervous system depends specificity of axonal connections, which occurs in 3 steps:

    Pathway selection – axons travel along a route that leads to a particular region of embryo

    Target selection – axons when reach correct area, recognize and bind to cells

    Address selection – internal patterns are refined and axons “fine tune” their connection to target cells
  19. Outgrowth Theory – Axon growth cone

    •Growth cone ‘feels” its way along the substrate, moves by elongation and contraction of filopodia called microspikes

    •Each microspike samples the microenvironment --> sends signals back to soma --> differentiate
  20. Pathway Selection
    Growth cone:  Locomotory organelle of the growing neuron that senses environmental cues

    • Contact guidance: Extracellular environment provides navigational information
    •     •Growth cones prefer to migrate on adhesive surfaces – glycoprotein Laminin paves the path cells – a growth promoting substance
    •    •Guidance is also provided by adhesion molecules, N-CAM, L1 etc
    •    •Semaphorin proteins also guide growth cones by selective repulsion

    Labeled Pathways: Contact guidance provides only general information

        -A given neuron can recognize the surface of another neurons that has grown out before it
  21. Target selection
    •Once neuron reaches the group of cells containing potential target, they depend on neurotrophins secreted by target cells for guidance.

    •Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3) – are short range chemotactic or chemorepulsive factors
  22. Address Selection
    • Synapse - specialized junction between axon and its target

    A. growth cone approaches developing muscle cells (has acetyl choline receptors)

    B. Axon releases Agrin --> clustering of ACh receptors

    C. Neurotransmitter vesicle enters axonal terminal – extracellular matrix connects the synaptic space

    D. Other axons converge on the same synaptic site

    E. Completion of muscle innervation