Platelet-activating factor acetylhydrolase expression and activity suggest a link between neuronal migration and platelet-activating factor

A hemizygous deletion of LIS1, the gene encoding alphaLis1 protein, causes Miller-Dieker syndrome (MDS). MDS is a developmental disorder characterized by neuronal migration defects resulting in a disorganization of the cerebral and cerebellar cortices. alphaLis1 binds to two other proteins (beta and gamma) to form a heterotrimeric cytosolic enzyme which hydrolyzes platelet-activating factor (PAF). The existence of heterotrimers is implicated from copurification and crosslinking studies carried out in vitro. To determine whether such a heterotrimeric complex could be present in tissues, we have investigated whether the alphaLis1, beta, and gamma genes are coexpressed in the developing and adult brain. We have isolated murine cDNAs and show by in situ hybridization that in developing brain tissues alphaLis1, beta, and gamma genes are coexpressed. This suggests that alphaLis1, beta, and gamma gene products form heterotrimers in developing neuronal tissues. In the adult brain, alphaLis1 and beta mRNAs continue to be coexpressed at high levels while gamma gene expression is greatly diminished. This reduction in gamma transcript levels is likely to result in a decline of the cellular concentration of alphaLis1, beta, and gamma heterotrimers. The developmental expression pattern of alphaLis1, beta, and gamma genes is consistent with the neuronal migration defects seen in MDS; regions containing migrating neurons such as the developing cerebral and cerebellar cortices express these genes at a particularly high level. Furthermore, we uncovered a correlation between gamma gene expression, granule cell migration, and PAF hydrolytic activity in the cerebellum. In this tissue gamma gene expression and PAF hydrolysis peaked at Postnatal Days P5 and P15, a period during which neuronal migration in the cerebellum is most extensive. Mechanisms by which PAF could affect neuronal migration are discussed.