Thursday 20 November 2003
Pathology (anomalies of neuronal migration) (Exemples)
periventricular cortical heterotopia
Neuronal migration and axonal targeting
Neuronal migration and axonal growth are crucial for generating the elaborate synaptic circuitry that is characteristic of the nervous system. In both invertebrates and vertebrates, immature neurons migrate along dorso-ventral and antero-posterior routes in the developing central nervous system, and in higher vertebrates neurons migrate in a unique radial pattern, primarily along GLIA, to form the cerebral cortex.
Cell migration is a three-step process that consists of leading-edge extension, nuclear translocation into the leading edge (nucleokinesis), and retraction of the trailing process; several lines of evidence place the centrosome at different steps in the process, and these roles are highlighted by the perturbation of nucleokinesis by mutations in centrosome-associated proteins.
It has been suggested that the centrosome determines the direction of migration by placing itself in front of the nucleus, facing the direction of movement from which microtubules emanate to project into the leading edge.
However, in Dictyostelium discoideum the centrosome adopts its position after the new PSEUDOPOD has formed. To achieve movement, D. discoideum forms numerous pseudopodia, but only the projection that is anchored by a centrosome survives, whereas the remainder are retracted; this indicates that the centrosome might in fact stabilize one pseudopod, thereby influencing the direction of movement.
It is possible that the sequence of events that lead to pseudopod elongation differs between D. discoideum and vertebrates, although this issue has not been addressed fully in vivo in mammals. What is clear, however, is that centrosomal function is crucial to cell motility across phyla.
Once the direction of migra-tion is determined, the centrosome is necessary for nucleokinesis, and the study of several human cortical dysplasias has highlighted the importance of the centrosome and its associated proteins during this step (See also: lissencephaly).
Kerjan G, Gleeson JG. Genetic mechanisms underlying abnormal neuronal migration in classical lissencephaly. Trends Genet. 2007 Dec;23(12):623-30. PMID: #17997185#
Guerrini R, Filippi T. Neuronal migration disorders, genetics, and epileptogenesis. J Child Neurol. 2005 Apr;20(4):287-99. PMID: #15921228#
Badano JL, Teslovich TM, Katsanis N. The centrosome in human genetic disease. Nat Rev Genet. 2005 Mar;6(3):194-205. PMID: #15738963#
Kato M, Dobyns WB. Lissencephaly and the molecular basis of neuronal migration. Hum Mol Genet. 2003 Apr 2 ;12(Suppl 1) :R89-96. PMID : #12668601#
Tear G. Neuronal guidance. A genetic perspective. Trends Genet. 1999 Mar;15(3):113-8. PMID: #10203809#