Neuronal migration

Like other motile cells, neurons migrate in three schematic steps, namely l eading edge extension, nuclear translocation or nucleokinesis, and retracti on of the trailing process. In addition, neurons are ordered into architect onic patterns at the end of migration. Leading edge extension can proceed a t the extremity of the axon, by growth cone formation, car from the dendrit es, by formation of dendritic tips. Among both categories of leading edges, variation seems to be related to the rate of extension of the leading proc ess. Leading edge extension is directed by microfilament polymerization fol lowing integration of extracellular cues and is regulated by Rho-type small GTPases. In humans, mutations of filamin, an actin-associated protein, res ult in heterotopic neurons, probably due to defective leading edge extensio n. The second event in neuron migration is nucleokinesis, a process which i s critically dependent on the microtubule network, as shown in many cell ty pes, from slime molds to vertebrates. in humans, mutations in the PAFAHIB1 gene (more commonly called LIS1) or in the doublecortin (DCX) gene result i n type 1 lissencephalies that are most probably due to defective nucleokine sis. Both the Lis1 and doublecortin proteins interact with microtubules, an d two Lis1-interacting proteins, Nudel and mammalian NudE, are components o f the dynein motor complex and of microtubule organizing centers. In mice, mutations of Cdk5 or of its activators p35 and p39 result in a migration ph enotype compatible with defective nucleokinesis, although an effect on lead ing edge formation is also likely. The formation of architectonic patterns at the end of migration requires the integrity of the Reelin signalling pat hway. Other known components of the pathway include members of the lipoprot ein receptor family, the intracellular adaptor Dab1, and possibly integrin alpha 3 beta 1. Defective Reelin leads to poor lamination and, in humans, t o a lissencephaly phenotype different from type 1 lissencephaly. Although t he action of Reelin is unknown, it may trigger some recognition-adhesion am ong target neurons. Finally, pattern formation requires the integrity of th e external limiting membrane, defects of which lead to overmigration of neu rons in meninges and to human type 2 lissencephaly. (C) 2001 Elsevier Scien ce Ireland Ltd. All rights reserved.