THE LISSENCEPHALY GENE-PRODUCT LIS1, A PROTEIN INVOLVED IN NEURONAL MIGRATION, INTERACTS WITH A NUCLEAR-MOVEMENT PROTEIN, NUDC

Important clues to how the mammalian cerebral cortex develops are prov ided by the analysis of genetic diseases that cause cortical malformat ions [1-5], People with Miller-Dieker syndrome (MDS) or isolated lisse ncephaly sequence (ILS) have a hemizygous deletion or mutation in the LIS1 gene [3,6]; both conditions are characterized by a smooth cerebra l surface, a thickened cortex with four abnormal layers, and misplaced neurons [7,8]. LIS1 is highly expressed in the ventricular zone and t he cortical plate [9,10], and its product, List, has seven WD repeats [3]; several proteins with such repeats have been shown to interact wi th other polypeptides, giving rise to multiprotein complexes [11], Lis 1 copurifies with platelet-activating factor acetylhydrolase subunits alpha 1 and alpha 2 [12], and with tubulin; it also reduces microtubul e catastrophe events in vitro [13], We used a yeast two-hybrid screen to isolate new Lis1-interacting proteins and found a mammalian ortholo g of NudC, a protein required for nuclear movement in Aspergillus nidu lans [14], The specificity of the mammalian NudC-Lis1 interaction was demonstrated by protein-protein interaction assays in vitro and by co- immunoprecipitation from mouse brain extracts, In addition, the murine mNudC and mLis1 genes are coexpressed in the ventricular zone of the forebrain and in the cortical plate. The interaction of Lis1 with NudC , in conjunction with the MDS and ILS phenotypes, raises the possibili ty that nuclear movement in the ventricular zone is tied to the specif ication of neuronal fates and thus to cortical architecture. (C) Curre nt Biology Ltd ISSN 0960-9822.