Platelet-Activating Factor Acetylhydrolase Expression and Activity Suggest a Link between Neuronal Migration and Platelet-Activating Factor

AbstractA hemizygous deletion ofLIS1,the gene encoding αLis1protein, 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. αLis1binds 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 outin vitro.To determine whether such a heterotrimeric complex could be present in tissues, we have investigated whether the αLis1, β, and γ genes are coexpressed in the developing and adult brain. We have isolated murine cDNAs and show byin situhybridization that in developing brain tissues αLis1, β, and γ genes are coexpressed. This suggests that αLis1, β, and γ gene products form heterotrimers in developing neuronal tissues. In the adult brain, αLis1and 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 αLis1, β, and γ heterotrimers. The developmental expression pattern of αLis1, 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