ABNORMAL CORTICAL DEVELOPMENT TOWARDS ELUCIDATION OF THE LIS1 GENE-PRODUCT FUNCTION (REVIEW)

Lissencephaly is a relatively common brain malformation. Lissencephaly type 1 is characterized by the smooth appearance of the cortex and th e presence of four abnormally positioned layers instead of the normal six. Lissencephaly is considered to be an abnormality in neuronal migr ation. The gene mutated in type 1 lissencephaly was cloned by us and d esignated LIS1. Recently, several genes involved in cortical developme nt have been cloned in the mouse. In human an additional X-linked liss encephaly gene has been identified. We summarize here our current know ledge on the LIS1 gene and its function. It has been identified as a n on-catalytic subunit of PAF-acetylhydrolase, a heterotrimeric enzyme w hich inactivates the platelet-activating factor (PAF). In addition, we have demonstrated that LIS1 interacts with tubulin, and affects the d ynamics properties of microtubules. LIS1 contains seven WD repeats and may structurally resemble the beta-subunit of heterotrimeric G protei ns. Interestingly, the catalytic subunit of PAF-acetylhydrolase was fo und to resemble the alpha-subunit of heterotrimeric G proteins. We rai se the possibility that LIS1 is part of an intracellular signaling pat hway involved in neuronal migration.