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

Abstract

A hemizygous deletion of LIS1, the gene encoding α(Lis1) 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. α(Lis1) binds to two other proteins (β and γ) 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 α(Lis1), β, and γ 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 α(Lis1), β, and γ genes are coexpressed. This suggests that α(Lis1), β, and γ gene products form heterotrimers in developing neuronal tissues. In the adult brain, α(Lis1) and β mRNAs continue to be coexpressed at high levels while γ gene expression is greatly diminished. This reduction in γ transcript levels is likely to result in a decline of the cellular concentration of α(Lis1), β, and γ heterotrimers. The developmental expression pattern of α(Lis1), β, and γ 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 γ gene expression, granule cell migration, and PAF hydrolytic activity in the cerebellum. In this tissue γ 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.