#14099 - Cns Migration - Neuroscience 1

Discuss the role for migration in the development of the central nervous system. How can disruption of migration result in developmental disorders?

Intro

• Migration of cells during development of CNS plays a key role in the formation of a functional CNS

• This is because correct spatial location of neurons ensure accurate synaptic contact with neighbouring and more distant neurons

• Mutations in the migratory process results in severe CNS disorders

Cerebral cortex

• Grey matter of cerebral cortex consists of 6 neuronal layers each with a specific function

  • Layer 4 receives input from the thalamus

  • Layer 5 projects to subcortical areas

• Within the cortex there are both excitatory glutamatergic and inhibitory GABAergic neurons- both of these classes of neurons arise from different areas of CNS and migrate by different routes

Excitatory glutamatergic

• Originate from the radial glial cells of the CNS – these cells are multipotent and have processes that attach to both the pia mater and to the ventricular surface

• On receiving neurogenic signals these cells undergo asymmetric division to give rise to a neuronal progenitor and another radial glia cell

• To show the proliferative capacity of these cells phosphohistone labelling was done and this showed a layer of dividing cells in the ventricular zone. This labelling technique also showed the presence of two additional layers which contained dividing cells: subventricular and outersubventricular layers and these contain the intermediate progenitors of the radial glia

  • These cells also give rise to cortical neurons and their importance is shown in Tbr2 KO models which often resulted in microcephaly in mouse models

• Once the excitatory neuronal progenitor is formed migration towards the pia mater occurs

• During the early stages of corticogenesis radial independent translocation occurs

  • In this process a large radial process of the neuronal progenitor which either emerges just before migration or is inherited from the radial glia cells attaches to the pial surface

  • Once this occurs the process of the neuronal progenitor attached to the ventricular surface detaches

  • This is then followed by cytoskeletal arrangements of actin in the leading process of the neuronal progenitor which causes the leading process to contract and pull the somal body towards the pia

  • To show that this occurs live imaging studies of corticogenesis has been done and it has been shown that during the early stages neuronal progenitors rapidly migrate to the surface in a fluid like motion

• During the later stages of corticogenesis radial migration proceeds by radial dependent dependent locomotion and relies on the radial glia to act as a scaffold for the migrating neuronral progenitors

  • Neurons undergoing this form of migration have free leading processes

  • Once these cells have been detatched from the ventricular surface, polymerisation of actin in the leading process causes it to extend towards the pia

  • Importance of cytoskeletal rearrangements have been shown in filamin-1 KO models in mice which lead to periventricular heterotopia

  • After the leading process has extended the neuronal progenitor makes transitatory connections with the radial glia. These interactions involve integrin receptors and ligands

    • Specific KO of either of these leads to severe migratory defects

  • Once adhesion occurs, the centrosome of the neuronal progenitor migrates to the leading process and forms a structure of microtubules which eminate around the nucleus. This structure is known as the perinuclear cage and is essential for the final stage of locomotion which is nucleokkinesis

  • Key regulatory protein of the microtubules that enables translocation of the nucleus is Lis1 which is a regulatory protein of platelet activating factor acetyl dehydrogenase. Mutations in Lis1 results in Lissencephaly type 1 – this results in a thicker grey matter with most of the neurons clustered in the deeper neuronal layers

  • Under live imaging- locomotion seen to occur in salutatory steps and this supports the idea of radial glia cells as scaffold cells on which temporary adhesive contacts are made

• In the cerebral cortex the 1^st layer of neurons to form is the molecular layer which is the Cajal Retzius cells

  • These cells lay an important role in the inside out arrangement of the cerebral cortex as they secrete the glycoprotein reelin. KO of the reelin gene which is specifically expressed in these cells results in progenitors piling on the inside of older cells instead of passing through them to form more superficial layers

  • So, earlier developed neuronal progeintors give rise to layers 6 and 5 whilst later formed progenitors give rise to layers 4-2

• Patterning of the cortex

  • Specific patterning of the cortex was proposed by Rakic who proposed the radial unit of development – who stated that 1 progenitor or small group of progenitors in the ventricular zone give rise to column of cells across the 6 layers of the cortex

  • Patterning of these radial units is mediated by FGF8...