GRADED REDUCTION OF PAFAH1B1 (LIS1) ACTIVITY RESULTS IN NEURONAL MIGRATION DEFECTS AND EARLY EMBRYONIC LETHALITY

Heterozygous mutation or deletion of the beta subunit of platelet-acti vating factor acetylhydrolase (PAFAH1B1, also known as LIS1) in humans is associated with type I lissencephaly, a severe developmental brain disorder thought to result from abnormal neuronal migration. To furth er understand the function of PAFAH1B1, we produced three different mu tant alleles in mouse Pafah1b1. Homozygous null mice die early in embr yogenesis soon after implantation. Mice with one inactive allele displ ay cortical, hippocampal and olfactory bulb disorganization resulting from delayed neuronal migration by a cell-autonomous neuronal pathway. . Mice with further reduction of Pafah1b1 activity display more severe brain disorganization as well as cerebellar defects. Our results demo nstrate an essential, dosage-sensitive neuronal-specific role for Pafa h1b1 in neuronal migration throughout the brain, and an essential role in early embryonic development. The phenotypes observed are distinct from those of other mouse mutants with neuronal migration defects, sug gesting that Pafah1b1 participates in a novel pathway for neuronal mig ration.