1. Adapted from:
Li-Huei Tsai
Joseph G. Gleeson
Catherine Lambert de Rouvroit
Andre G. Goufinet

2. During development neurons migrate from the subventricular
area of the brain to the surface of the brain under the
influence of glia produced
-chemoattractants or
-chemorepellents
During embriogenesis neurons migrate approximately 2 cm
(hundreds of cell body distances) to their final destination.

3.  Many human neurologic diseases are directly or
indirectly linked to disordered neuronal migration.
 Many genes that have been found to play critical roles
in neuronal migration during development also
appear to be central to the pathogenesis of
neurodegenerative disorders in the adult.
 In epilepsy and schizophrenia there is evidence that
disordered neuronal migration may contribute to the
pathogenesis, as one of the more frequent findings
in these conditions is heterotopically located neurons
in various positions of the CNS.

4.  Neuronal migration occurs in three stages:
1. Leading Edge Extension
2. Nuclear Translocation (Nucleokinesis)
3. Retraction of Trailing Process

5. Leading edge extension is directed by actin polymerization (directed
by attractive or repulsive extracellular cues). It is regulated by Rho
type small GTPases.
In humans, mutations of filamin (an actin-associated protein), result
in heterotopic neurons, probably due to defective leading edge
extension.

6.  Nuclear translocation is composed of
two sub-phases:
-Centrosome Positioning
-Movement of the nucleus towards the
centrosome
 As the neuron migrates there are
major cytoskeletal alterations in the
actin and microtubule (MT) cytoskeletons.
 Microtubules appear to emanate from a
single location (centrosome) just in
front of the nucleus and to extend
anteriorly into the leading process and
posteriorly to envelop the nucleus.

7. Lis1 and nucleocortin proteins interact with the microtubules.
Dynein is a microtubular molecular motor composed of 2
proteins: Nudel1 and NudE.
Lis1 protein interacts with dynein (Nudel1 and NudE ) proteins.
Defects in dynein activity lead to alterations in nuclear-centrosome coupling.

8.  In humans, mutations in the LIS1 or doublecortin (DCX) gene result in type 1
lissencephalies (which literally means smooth brain) caused by defective
neuronal migration during the 12th to 24th weeks of gestation resulting in a
lack of development of brain folds and grooves.

9.  The end of migration requires the integrity of the Reelin
signalling pathway.
 Reelin is thought to trigger recognition-adhesion among
target neurons.
 Other known components of the retraction of the trailing
process include members of the lipoprotein receptor
family Dab1, and possibly integrin alpha 3 beta 1.
 Deffects of the external limiting membrane lead to
overmigration of neurons in meninges (type 2
lissencephaly).