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 alpha(Lis1) protein, causes Miller-Dieker syndrome (MDS). MDS is a developmental disorder c haracterized by neuronal migration defects resulting in a disorganizat ion of the cerebral and cerebellar cortices. alpha(Lis1) binds to two other proteins (beta and gamma) to form a heterotrimeric cytosolic enz yme which hydrolyzes platelet-activating factor (PAF). The existence o f heterotrimers is implicated from copurification and crosslinking stu dies carried out in vitro. To determine whether such a heterotrimeric complex could be present in tissues, we have investigated whether the alpha(Lis1), beta, and gamma genes are coexpressed in the developing a nd adult brain. We have isolated murine cDNAs and show by in situ hybr idization that in developing brain tissues alpha(Lis1), beta, and gamm a genes are coexpressed. This suggests that alpha(Lis1), beta, and gam ma gene products form heterotrimers in developing neuronal tissues. In the adult brain, alpha(Lis1) and beta mRNAs continue to be coexpresse d at high levels while gamma gene expression is greatly diminished. Th is reduction in gamma transcript levels is likely to result in a decli ne of the cellular concentration of alpha(Lis1), beta, and gamma heter otrimers. The developmental expression pattern of alpha(Lis1), beta an d gamma genes is consistent with the neuronal migration defects seen i n MDS; regions containing migrating neurons such as the developing cer ebral and cerebellar cortices express these genes at a particularly hi gh level. Furthermore, we uncovered a correlation between gamma gene e xpression, granule cell migration, and PAF hydrolytic activity in the cerebellum. In this tissue gamma gene expression and PAF hydrolysis pe aked at Postnatal Days P5 and P15, a period during which neuronal migr ation in the cerebellum is most extensive. Mechanisms by which PAF cou ld affect neuronal migration are discussed. (C) 1996 Academic Press In c.