NEURONE MIGRATION

1

• NEURONE MIGRATION
• Neurones born distant from final location must
  migrate
• Migration lays down the layers of the laminated
  (layered) cortex
• earliest to migrate laid down first
• later generated neurones pass by earlier ones.
• Ones nearest cortical surface are the last to
  have migrated.
• Single cells migrate variable long distances - up
  to mms.
• 3 types of migration - gliophilic neurophilic
  biphilic
• Gliophilic - migrate along pre-fromed fibres
• eg. radial glial fibres - bundles of elongated
  radial glia span entire thickness of cortex
  several mm
• successive generations of neurones migrate
  OUTWARDS along same glial track to end up in
  appropriate laminar position.
  (handout Fig 1)
• Radial glia are transient cells - once migration
  is complete, either degenerate or become
  astrocytes.

2

• Neurophilic (Handout Fig 2)
• some migrating neurones ignore glia and adhere
  preferentially to nearby axons. Neurones migrate
  along brain stem surface to pons - bypass radial
  glial fibres on the way, ignore them
• Biphilic
• Combined -- gliophilic and neurophilic
  properties
• eg cerebellar granule cells migrate INWARDS from
  proliferative zone in external granule layer,
  just below pial surface membrane - establishes
  anatomy of cerebellum
• (see Figs. 3 4).
• Final division of Granule cells - in molecular
  layer - then
• become bipolar by extending horizontal processes
  along parallel fibres of a previous granule cells
  
• occurs parallel to pial surface and at right
  angles to Purkinje cell dendrites (this is the
  neurophilic part)
• Next cell becomes tripolar
• attaches a vertical process to the shaft of a
  Bergmann glial fibre (radial glial equivalent in
  cerebellum - not attached to both pia and
  ventricle surfaces - cell body in Purkinje layer
  is called Golgi epithelial cell) this is the
  gliophilic part.
• Once vertical process of sufficient length
  nucleus migrates through its own process - entire
  cell body passes through interwoven mesh of
  processes in molecular layer.
• Again many successive generations follow same
  glial fibre.

3

• Granule cell migration creates the cellular and
  synaptic architecture of the cerebellum
• because the horizontal and vertical segments of
  the cell are left behind after nuclear migration
  and become the parallel fibres and vertical shaft
  of the T-shaped granule cell axon This makes
  synapses with Purkinje dendrites.
• Again anatomy reflects developmental timescale
• the depth of parallel fibres in molecular layer
  reflects the time of differentiation.
• Deepest - first granule cells to migrate
• closest to pial surface - most recent
• 2 issues
• 1. How does the cell surface segregate the
  molecules that drive neurophilic movements of 2of
  the 3 neurites and gliophilic movements of 1of
  the 3 neurites?
• 2. What drives the inward migration of the
  nucleus?
• Specific cell adhesion molecules (glycoproteins)
  promote specific cell-cell attachments.
• N-CAM (nerve cell adhesion molecule) stains all
  neurones in all layers - non specific so no
  guidance role.
• BUT isoform NCAM - PSA (poly sialic acid) is
  distributed differentially.

4

• Not present in proliferative zone - does stain
  both cell bodies and leading process of migrating
  neurones also stains Bergmann glial radial fibre.
  Staining remains until migration complete and
  synapses formed - then lost.
• Antibodies to NCAM-PSA block granule cell
  migration
• Other CAMs involved also.
• Antibodies to Ng-CAM to cytotactin - inhibit
  migration - at different time points
• slice cultures
• anti NgCAM inhibits migration out of external
  granule layer - early on in process
• d 0-1.5 effective d 1.5-3 NOT effective
• ab cytotactin - inhibition effective later on
• d 0-1.5 poor inhibition d 1.5 - 3 good
  inhibition.
• So conclude
• Early migration/contact with/binding to Bergmann
  glia requires Ng-CAM
• later migration through molecular layer requires
  cytotactin.

5

• Migration fails in some mutations
• weaver mice - cerebellar granule neurones fail
  to migrate, and die in ectopic sites.
• Is this a problem with the neuron or with glial
  cells?
• Co-culture normal / weaver tissues in
  combinations
• Normal neurones migrate on normal and weaver
  glia
• weaver neurones do NOT migrate on either - fail
  to attach defective neuronal adhesion.
• Migration also fails due to some environmental
  factors
• In development of the cerebral cortex, groups
  of 90 cells coupled to each other by gap
  junctions in proliferative (ventricular) zone.
• Cells from same proliferative area use same
  radial glial guide to enter cortex
• creates developmental (ontogenetic) column of
  neurones
• ventricular zone is a pre-parceled, mosaic map
  of proliferative units - fate map of future
  cortex (Fig.5)
• Columnar arrangements in cortex leads to groups
  of cortical cells expressing specific marker
  molecules because of their clonal origins and
  because they used the same glial guides and were
  previously coupled by gap junctions.

6

• 2 basic types of cortical malformations when
  migration fails
• 1. lissencephalic
• smooth cortex normal thickness but reduced area
  
• number of ontogenetic columns is greatly reduced,
  but there are a normal number of neurones in each
• This is due to early defects when proliferating
  units are forming in the ventricular zone - in
  humans damage during first 7 weeks of gestation
  can wipe out many proliferative units
• 2. polymicrogyria
• cortex is convoluted but much thinner and of
  normal area
• numbers of ontogenetic columns are normal but
  much reduced number of neurones in each
• Defects arise after the normal number of
  proliferative units are formed - in humans post 7
  weeks of gestation
• This is due to defective neuron migration -
  leading to reduced numbers of neurones in each
  ontogenetic column.

7

• Radiation of humans embryos leads to brain
  malformations
• These are a direct result of neuronal
  proliferation / migration defects.
• Many born with small heads and mentally retarded
  -
• examples where exposed foetally at 2 months
  gestation and lived for 16 yr - then post mortem
• small thin brain, much of superficial layers
  missing - migration had been compromised.
• but also large areas where ectopic neurones have
  survived in the wrong places - in sub cortical
  areas close to ventricles (proliferative areas).
• These have never migrated, but survived in
  ectopic sites and made incorrect synapses.
• Experimental model - irradiation of rats
• also results in survival of ectopic neurones
• remarkably some from ventricular proliferative
  zones still project down spinal cord
• these would have been part of cortico-spinal
  projections still make spinal projection - but
  not from cortex, from subcortical ventricular
  area.
• Never migrated correctly, but some are capable of
  doing axonal elongation and projection correctly.