LIS1 and dynein motor function in neuronal migration and development.

Neuronal migration has been studied extensively for over 30 years in diverse mammalian species from the mouse to human. The sequence of events that occurs during cortical development is shared by all of these species (for reviews, see Gleeson and Walsh 2000; Walsh and Goffinet 2000). At the time of neurogenesis, neural precursors proliferate and differentiate into young postmitotic neurons. These postmitotic immature neurons migrate from the ventricular zone (VZ) to a layer called the preplate at the surface of the developing cerebral cortex. The first migrating neurons split the preplate and form the cortical plate, which develops into the cortex. As migration from the VZ continues, cortical lamination is established in an inside-out fashion. The earliest-born neurons end up deep in the cortex, as later-born neurons migrate past them toward the pial surface to establish more superficial layers of the cortex. The latest-born neurons reside near the pial surface. In the final stages of cortical development, synaptogenesis and apoptotic elimination of populations of neurons occur. Physically, the migration of neurons require the same three steps necessary for migration of any cell: The extension of the leading edge that explores its environment for attractive and repulsive signals; the movement of the nucleus into the leading process, called nucleokinesis; and the retraction of the trailing process. The understanding of the process of mammalian neuronal migration resulted primarily from neurobiological studies of brain development in normal mammals and mutant mice such as reeler. These studies provided important insight into the laminar development of the CNS. However, they did not identify the genetic and developmental pathways that regulate neuronal migration. Cloning of disease genes for human neuronal migration defects and mouse mutants have provided critical entry points into these pathways, whereas genetic and cell biological studies have guided our understanding of the function of these gene products in neuronal migration. For example, cloning of the gene mutated in reeler and the identification of its protein product RELN led to the elucidation of a RELN-dependent signal transduction pathway (for recent review, see Rice and Curran 1999). Other genes have been identified that are responsible for neuronal migration defects in the human (LIS1 and DCX) and mouse (Cdk5 and its required activators p35 and p39), but until recently, the relationship between these genes involved in migration were unknown. Several recent studies have demonstrated that LIS1, the protein product of a gene mutated in the human neuronal migration defect lissencephaly, binds to and regulates dynein motor function in the cell. These studies place LIS1 in the midst of a well-studied motor complex important for several critical cell functions and perhaps provide a context for integrating several neuronal migration pathways. In this review, we will provide some background on the human and mouse studies that provided the entry points to neuronal migration pathways, the investigation of gene function in model systems, and what these studies tell us about the mechanisms regulating neuronal migration. We will focus on the recent studies of LIS1 function and how they can potentially integrate other known pathways of neuronal migration.