Lissencephaly is a congenital brain malformation manifested by a smooth cerebral surface due to incomplete neuronal migration (Dobyns, 1989). Type I lissencephaly occurs either as an isolated abnormality or in association with dysmorphic facial appearance in Miller-Dieker syndrome

Lissencephaly is a congenital brain malformation manifested by a smooth cerebral surface due to incomplete neuronal migration (Dobyns, 1989). Type I lissencephaly occurs either as an isolated abnormality or in association with dysmorphic facial appearance in Miller-Dieker syndrome (MDS; Miller, 1963; Dieker, 1967). Lissencephaly patients usually die young with profound mental retardation, muscle weakness and seizures. One causal gene for lissencephaly, lissencephaly 1 (LIS1), encodes a protein containing seven WD-40 repeats (Reiner et al., 1993). Heterozygous deletions or mutations in the LIS1 gene have been identified in patients with MDS and isolated lissencephaly (Reiner et al., 1993; Lo Nigro et al., 1997), indicating the haplo-insufficiency of LIS1. Mice homozygous for a null Lis1 mutation die early in embryogenesis soon after implantation. Heterozygous and compound heterozygous mice have dosage-dependent defects in neuronal migration and neurogenesis (Hirotsune et al., 1998). Lissencephaly is also caused by mutations in an X-linked gene encoding a potentially phosphorylated protein that may play a role in a signal transduction pathway overlapping with the function of LIS1 (des Portes et al., 1998; Gleeson et al., 1998). LIS1 was also identified biochemically in bovine brain extracts as the regulatory subunit α of platelet-activating factor acetylhydrolase (PAFAH; Hattori et al., 1994). PAFAH contains two additional catalytic subunits β and γ, and the crystal structure of the β subunit closely resembles that of GTPases (Ho et al., 1997). PAFAH catalyzes the removal of the acetyl group at the sn-2 position and produces biologically inactive lyso-PAF. PAFAH thus is important for regulating levels of the active PAF, which has potent biological functions in diverse organs (Venable et al., 1993), including the central nervous system (Kornecki and Ehrlich, 1988; Bito et al., 1992; Marcheselli and Bazan, 1994). A function for PAFAH in the brain is also suggested by the observation that LIS1 and the two catalytic subunits are highly expressed in the same developing brain tissues (Mizuguchi et al., 1995; Albrecht et al., 1996). Since PAF is membrane localized (Vallari et al., 1990), it is possible that the role of LIS1 is to localize the two catalytic subunits (β and γ) of PAFAH to the plasma membrane. LIS1 has been shown to associate with tubulin (Sapir et al., 1997) and β-spectrin (Wang et al., 1995), to co-localize with microtubules in tissue culture cells, and to reduce microtubule catastrophe frequency in vitro (Sapir et al., 1997). A LIS1 homolog, nudF (Xiang et al., 1995), was isolated in a screen for nuclear migration mutants in Aspergillus nidulans. NudF interacts genetically with nudC, another nuclear migration gene in A. nidulans (Osmani et al., 1990; Xiang et al., 1995). NUDC is required to maintain a normal concentration of NUDF protein (Xiang et al., 1995). The murine NUDC homolog and Lis1 are co-expressed in the ventricular zone of the forebrain and in the cortical plate, and they also interact in a two-hybrid system (Morris et al., 1998b), suggesting that nuclear migration may play an important role for neuronal or cell migration (Morris et 4477 Development 126, 4477-4488 (1999) Printed in Great Britain © The Company of Biologists Limited 1999 DEV5361