Transcript 4Neuronal Migration

Neuronal Migration in CNS
Development
After neurons are born, they migrate
to their final destinations:
Radial migration
Tangential migration
Radial migration along radial glia cells
in the developing CNS:
Serial section electron microscopy:
Migrating neurons in the intermediate zone are
intimately apposed to radial glial fibers (striped
vertical shafts, RF1-6), which extend short
lamellate expansions (LE) at a right angle to their
main axis. Nuclei (N) of migrating neurons are
elongated, and their leading processes (LP) are
thicker and richer in organelles than their trailing
processes (TP). Each leading process extends
several pseudopodial endings (PS). Several cross
sections through a migrating neuron are shown (a–
d); migrating cell partially encircles the shaft of the
radial glial fiber and these intimate contacts are
continuous throughout the length of the cell. OR,
optic radiation, From Sidman and Rakic (1973).
Radial migration along radial glia in the developing
Cerebellum, Hippocampus and Cortex
Migrating neurons are apposed to glia
Cells, which guide them from the ventricular zone to their final destination.
In vitro migration of hippocampal neurons
along the process of astroglia cells from
the cerebellum. Neurons can migrate along
a variety of radial glia fibers.
Cortical neurons are migrating over long
distances
Diagram of various trajectories taken by
migrating cortical cells co-generated at the
same embryonic day, but destined to settle
in various areas of the cortical plate.
Some cells generated in the neocortical
neuroepithelium migrate in the lateral
cortical stream for four or more days before
reaching their target destination.
The role of the Reelin
protein in cortical
development.
A) Reelin is expressed by Cajal Retzius cells
in the outer layer of the developing cortex. As
neurons migrate out along the glial fibers,
Reelin is proposed to organize the cortical
plate.
B) Reelin binds to a receptor, VLDLR or
ApoER2 in the surface membrane, which
leads to downstream signaling via Dab1,
resulting in alterations in gene expression. In
addition, Cdk5 phosphorylates cytoskeletal
components such as tau and neurofilaments,
which may affect organization of the
cytoskeleton and properties of migrating
neurons.
Procadherins act as another class of reelin
receptors.
Players in the formation of the neuronal layers of cerebral
cortex.
Layer 1 (Cajal-Retzius cells, blue), secrete Reelin.
Cells migrate along the radial glia (green) using genes that provide
components of the cytoskeleton (Lis1, Dcx, Filamin1, and Cdk5/p35) or
neuron-glia binding (Astn1, and Integrin 3).
Mutations in any of these genes results in brain malformations.
ME Hatten, 2002
• A cell’s position in the embryo is important in
development because its differentiation is
often dictated by location.
• A cell’s final location is important because
neural function depends on precise
connections between neurons and their
targets; presynaptic and postysynaptic
elements must be in the right place at the
right time.
• The final position in vertebrates requires
active migration.
• In the CNS (neural tube origin), development
builds from a basic columnar organization of cells.
• Many of the structures vary in the degree of
layering: cerebral cortex (6), hippocampus,
cerebellar cortex (simpler 2 layer arrangement),
retina, spinal cord (2-3) are layered in their final
development.
• Show several brain areas including subdivisions of
vesicles.
• This laminar structure is essential for the
formation of complex circuits.
• Structures that are not layered: brainstem,
midbrain, diencephalon.
• As a result, one important aspect of the
migrating movements = radial migration:
• A special class of cells, radial glial cells, are
differentiated for this purpose.
General Movement Pattern and
Building of Basic Embryonic Zones
• Cells becoming post-mitotic earliest end up in the
deepest cortical layers (3H-thymidine autorad) .
• The wall of the neural tube and its various
vessicles begins 1 cell deep.
• [the ventricular zone – replication and migration
will be outward]
• One of the 1st cells to differentiate is the radial
glial cell, with processes reaching outward to
span the thickness of the wall of the growing
brain vessicles. These provide a scaffold for the
dividing cells to migrate away from the
ventricular zone.
• As cell division progresses, the cortical
structure progresses from a simple
neuroepithelial sheet to a multi-laminar
structure.
• Illustrate here.
• Preplate: 1st step for early dividing cells to
migrate to (single layer) (post-mitotic neuronal
precursors).
• Intermediate Zone: between ventricular zone
and preplate containing the axons of these
neurons.
Marginal zone (future Layer I)
Preplate
Subplate = a transient pop
of neurons that largely
by apoptosis in early in postnatal life.
• What mechanism halts the migration of postmitotic neurons and induces them to form
layers?
• Studies of a mutant mouse, reeler, have
provided some clues. Mouse gets its name
because of disruption of the formation of
embryonic layers leads to cerebellar
disfiguration (recall earlier slides about
reeler).
• The mutated gene encodes an ECM-related
protein, called reelin.
• This suggests that ECM molecules may
function in the arrest of radial migration and
Primary Radial Migrations Along Glial
Fibers
• The close apposition of post-mitotic neurons
to the glial processes and the timing of their
appearance (revealed by detailed 3-D
reconstruction studies) led to proposal that
they are a substitute for primary migration of
neurons in the cortical structure in which they
appear.
• This can be a very long journey (3,000 μm in
primates.
• Illustration: neuron takes on a very extended
bipolar shape.
• EM studies have revealed specialized “migration
junctions” between the neuron soma and glial
fibers (interstitial junctions) – widening of
intercellular space with filamentous material,
which is contiguous with submembrane
cytoskeletal elements.
• A receptor system highly expressed in this stage
of development: astrostatin (neuronal
glycoprotein).
• Earlier studies: the function of radial glia have
stemmed from another neurological mouse
mutant, weaver, whose granule cells never
migrate out to their final location and was found
to involve a defect in cerebellar radial glia.
Secondary Migration
• In many brain areas, more complex secondary
migrations occur after the initial establishment of
a cortical scaffold.
• The example we will examine is the 2° migration
of granule cells in the developing cerebellar
cortex.
• As alluded to earlier, granule neurons do undergo
a 1° migration from ventricular zone with
assistance of radial glia (known to be disordered
in _____________ mutant mouse.
• Cortex example follow-up: In general, the 2°
germinal zone in a subventricular zone
overlaying the ventricular zone (illustrate
here).
• This has developed evolutionarily to supply
the large #s of neurons later in development
(in the human, 2° neurogenesis occurs
through the 2nd yr of life.
• What is the significance of this in terms of
trauma or pathology (e.g., stroke)?
In Cerebellum
• Dividing precursor cells stream across a
structure, known as the rhombic lip, then onto
the surface of the developing cerebellum,
establishing a 2° (displaced) germinal zone,
known as the external germinal layer (EGL).
• During prenatal development, this zone
develops over the entire surface of the
cerebellum 2 cells thick. After birth, rapid
proliferation expands the EGL  8 cells.
• Next, the downward migration of cells to the
final position (internal granular layer) by 15
days after birth.
• Recent molecular biology studies have
demonstrated that the separation of this
superficial zone of dividing cells and internal
zone of differentiating cells is accompanied by
expression of genes that are differentially
regulated at the transcriptional level:
• Different genes are transcribed during:
1. Neurogenesis
2. Initiation of neuronal differentiation
3. Axon outgrowth
4. Forming synaptic connections
Cell Migration Patterns Reflect
Neuronal Fate Specification
• As noted earlier, 3H-thymidine labeling studies
showed that layers of neurons are generated
in an “inside out” pattern.
• [Recall: 1st post-mitotic neurons settle in the
deepest layers to differentiate; later, they
migrate through these to more superficial
layers]
How do Cells Know when to Start
Differentiating?
1. Cells might possess an “internal clock” –
measure time or # of divisions.
2. Cells might be signaled by their local
environment (“community” to start
differentiating.
The latter is most supported in modern tissue
culture studies:
e.g., progenitor cells would “switch” their fate when
transplanted (i.e., an “internal timing”
mechanism would not be able to explain this).
A Few Notes Regarding Cell Migration in
Nonlayered Structures
• In brainstem and diencephalon, the final adult
structure is not layered.
• In these structures, cells still migrate outward
from a ventricular zone, but they aren’t
directed radially by glial fibers.
• Rather, they aggregate into nuclei or
condensed group of cells, all geared towards a
particular function (e.g., thalamus, brainstem,
hypothalamus).
• One clue to the way this can occur is with
cadherins, expressed by these cells;
e.g., R-cadherins.
• 2° migrations are used here to allow great cell
proliferation later in development.