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Siegfried Wagner

Well done 6/8

Describe the major patterns of cell migration in the development of the cerebral cortex.
How do the molecules that direct migration work and what can go wrong with them?

Through a complex interplay between cells and molecules, neuronal migration directs the
movement of different neural progenitors mostly postmitotic cells to their appropriate areas. As
has been identified in several pathologies, a slight discrepancy of any one factor can result in a
marked change of configuration in the cerebral cortex. Some of these chemicals have been
found to act in all aspects of migration while others exert their effects at a specific location and
time. Since the first studies into this intricate process were studied, research has subsequently
revealed a substantial catalogue of mediators, which have been implicated in a wide range of
neurological conditions.
Neuronal migration begins early in embryonic development. Following closure of the neural
tube, the anterior segment begins to proliferate and resemble an enlarged vesicle, termed the
prosencephalon. After cellular division and migration, the epithelial layer in the wall of this
division of the CNS will develop into the structures of the forebrain. The first step in
establishing the familiar cortical arrangement of the adult brain involves an apical-basal
movement, known as interkinetic nuclear migration, where cells replicate DNA in one section of
the ventricular zone and divide in another. Yes but this doesn’t really have anything to do with
migration per se By changes in the duration of different phases of mitosis, neural progenitors go
from an early proliferative stage giving rise to more precursors, to adopting asymmetric mitosis
resulting in cells that differentiate into neurons. These daughter cells of asymmetric cell division
migrate to form the first layer outside the ventricular zone, the pre-plate. The next migration
group separates the pre-plate into two layers, the marginal zone and the subplate, the former
containing reelin-producing neurons known as Cajal-Retzius cells and the latter acting as a
“scaffold” to cerebral development. Each subsequent migration of neurons establishes another
layer of the cortex, however this is always done in an inside-out pattern so that those neurons
migrating later form more superficial layers. Pasko Rakic observed this by injecting thymidine
into the cortex and demonstrating that an early injection was illustrated as a deeper layer
becoming stained while a late one was perceived in a more superficial layer. Loss of this inside-
out arrangement can be seen in reelin-deficient mice. Each consecutive migration of neural
progenitors passes the subplate but not the marginal zone, perhaps as a result of the secreted
molecules from the most superficial layer. Unhealthy Cajal-Retzius cells, the agents responsible
for reelin production, lead to no splitting of the preplate and an inverted cortex. This matrix-
bound protein binds to the lipoprotein receptors, VLDLR and ApoER2 resulting ultimately in
the phosphorylation of Dab1 and activation of src-kinases. GOOD Appropriately, mice with
defective Dab1, ApoER2 and VLDLR genes are phenotypically similar to reelin knock out
mice. Its role has not yet been confirmed however it has been implicated in microtubule
stabilization, Tau phosphorylation, neurite morphogenesis as well as many other components.
Some studies suggest it acts as a signal for migrating neurons to detach from radial glial
processes or that it might behave as a chemoattractant.
Translocation of neural progenitors in the prosencephalon from the ventricular zone to their
target layer can occur either along the radial axis of the neural tube (radial migration), or
orthogonal to it any angle, as long as it crosses radial glia (tangential migration). In addition it
has been shown that a cell may utilize both routes to reach its target. Some interneurons migrate
tangentially to the ventricular zone and then radially towards the pia.
Roughly 90% of neurons migrate radially to their zones guided by radial glial cells (ref?).
These neural progenitors stretch out, projecting a process to the pial surface while their cell
body lies in the ventricular zone. Cells can migrate either through somal translocation or
locomotion. In somal translocation, the branched leading edge is bound to the pial surface and
the cell body is pulled upwards through contraction of this extension while in locomotion, a
shorter unbranched neurite is projected towards the pial surface and there is no change in length
during migration. Good Tangential migration has been shown to be the method of translocation
by subpallial oligodendroglia and GABA-ergic interneurons. At the moment, two tangential
paths have been

identified, one from the medical ganglionic eminence (MGE) to the hippocampus and cerebral
cortex, the other from the lateral ganglionic eminence (LGE) to the olfactory bulb. While the
former subsides, the latter can still be seen in adults as the rostral migratory stream.
Neurotransmitters play a role in the development of tangential migration routes. Crandall et al
used brain slice preparations from knock out mice to show that dopamine plays a major role in
neurogenesis and tangential migration. Depending on the pharmacological manipulation, they
were able to augment and inhibit GABA neuron migration through D1 and D2 receptor
activation respectively. In addition, they had previously shown that slices from mice treated in
utero with cocaine, a blocker of dopamine reuptake and thus disruptor of dopamine receptor
function, resulted in fewer cells migrating along the tangential route from the basal forebrain.
Good
The cellular mechanisms, which occur in migration, mirror those in axon growth and guidance
and can be classed into three distinct steps. Initially the progenitor must extend its leading edge
exposing the neurite to its extracellular environment. The finger-like projecting filopodia,
composed containing of actin bundles, will grow or retract depending on the guidance cue
bound. Some, such as cadherins, promote extension, while others cause the neurite to contract
e.g. semaphorins. Movement occurs through local protein synthesis. mRNA has been identified
in the leading extension and blocking synthesis via anisomycin eliminates any attraction or
repulsion by guidance cues. Following stabilization of the neurite, the centrosome is moved into
the leading extension followed closely by the nucleus. Finally the end process is pulled in.
Each stage represents a new collection of molecules driving a separate process. The
importance of actin and the cytoskeletal elements, which interact with it, is evident in conditions
where its activity is hindered. Upon binding to an attractive ligand cue, actin anchorage in the
neurite occurs allowing myosin molecules at the base of the filopodium to contract moving the
soma towards the leading edge. By impeding the actin network with cytochalasin B, which
shortens actin filaments and stops formation of microfilaments, neuronal migration can be
completely halted. Clinically, the rare condition periventricular heterotopia results from a
mutation in the gene of one of actin's associated proteins, filamin A. It is manifested as epilepsy
and intellectual disability and radiology shows there to be clumping of grey matter along the
lateral ventricles. This cross-linking protein has a role in actin microfilaments and the regulation
of GTPases.
Microtubules have a pivotal role in most areas of neuronal migration but especially in leading
edge process extension and nucleokinesis. The vast number of microtubule-associated proteins
(MAPs), which stabilize microtubules, and their binding molecules, has led to the discovery of a
plethora some of disorders targeting this pathway. Type 1 lissencephaly is perhaps one of the
most common neurological conditions resulting from a defective MAP. Deletion of the gene
Lis1 leads to a smooth brain usually with only four layers of cortex, lacking the normal amount
of gyri and sulci. It has been identified as important in a few areas: Lis 1 encourages stability of
microtubules by reducing catastrophe and associates with the MAP Ndel1, which together
regulate dynein networks thus facilitating centrosome interaction with the nucleus. It is even
believed to act on a lipoprotein receptor originally activated by reelin. In severe cases a mutation
in Lis 1 as well as other genes such as 14-3-3ε can lead to Miller-Dieker syndrome. As well as
the smooth appearance characteristic of lissencephaly, there are craniofacial dysmophisms such
as microcephaly and micrognathia. The MAP doublecortin (DCX), which is expressed solely in
immature neurons, has also been implicated in some human conditions and plays a role in
microtubule stability. A mutation in DCX, located on the X chromosome, is the underlying
cause for X-linked lissencephaly in men while in women it presents as subcortical laminar
heterotopia, where an extra layer of neurons can be found in the white matter. More recently
mutations in the microtubule constituent, alpha tubulin, have been shown to also result in
lissencephaly in humans. Keays they got mice from Harwell which had this done et al injected
mice with N-ethyl-N-nitrosurea (ENU) leading to randomized mutagenesis in the sperm and
examined the resulting offspring with neuronal migration defects. By analysing human
homologs of the murine genes involved, they found that

a mutation in the TUBA3 gene led to mental retardation, severe epilepsy and other
lissencephalic symptoms. Their research suggests the point mutation disrupts heterodimer
formation of tubulin however this is yet to be confirmed.
Much controversy still surrounds whether neuronal migration pathologies can be a result of
extracellular cue impairment. Although molecules such as netrins, semaphorins and Slit2 are
involved in neuronal migration, not much has been elucidated about their relevance
pathologically in humans. Netrins are now believed to activate a form of glycogen synthase
kinase (GSKβ) and to ultimately promote MAP1B phosphorylation, an important modulator of
microtubule assembly. Netrin defects are yet to be see in humans. Semaphorins are implicated in
tangential migration and their receptors maintain actin networks and microtubule assembly. Slit2
and its receptor Robo are known to act as a repellent and attractant network ultimately
regulating actin filaments.
Lissencephaly type 2, also known as cobblestone lissencephaly, comprises three diseases with
muscular dystrophy effects and a different aetiology to type 1. The most severe form is Walker-
Warburg syndrome (WWS) where severe retinal and cerebral malformations, cerebellar
hypoplasia, and encephalocoeles result in very low life expectancy. WWS can result from a
mutation in either the Protein-O-mannosyltransferase 1, 2 or FKTN gene. While the first two
genes are involved in cell rigidity and integrity, fukutin is responsible for glycosylation of a
component of carbohydrates in skeletal muscle. Mutations in FKTN or an associated gene
FRKN cause Fukuyama type congenital muscular dystrophy. The third disease, muscle eye brain
disease, can result from a mutation in FKRP, POMGnT1, or LARGE.
A wide range of molecules are involved in neuronal migration. Modulation of any of these can
result in highly detrimental effects and therefore understanding of the mechanisms involved may
reveal pathways, which could be exploited clinically as treatment options. In most cases, the
conditions such as lissencephaly are hugely disabling and lead to a poor quality of life.
Therefore more research should be done into the causes of migration defects and what can be
done to address them.

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