LIS1 Let's Interact Sometimes… (Part 1)

potentially intriguing relationships between LIS1 and mi-Orly Reiner* crotubule regulation, microtubule-based motor pro-Department of Molecular Genetics teins, and migration (reviewed in Morris et al., 1998a). The Weizmann Institute of Science NudF, a LIS1 homolog in Aspergillus nidulans, was ini-76100 Rehovot tially identified as a mutant defective in nuclear migra-Israel tion (Xiang et al., 1995). NudF is required for nuclear translocation and interacts with subunits of cytoplasmic dynein, a microtubule-based motor protein. Mutations Introduction in tubulin suppress mutations in a number of genes in LIS1 was identified as the gene mutated in a severe this pathway. Mammalian homologs of genes involved human developmental brain malformation known as lis-in this pathway have been shown to interact with LIS1. sencephaly (" smooth brain ") type 1. Patients with lis-For instance, nudC, a protein that controls the levels of sencephaly are often severely retarded, epileptic, and nudF in Aspergillus nidulans, interacts with LIS1 (Morris die at a young age. The most striking feature of the et al., 1998b). In addition, experiments using mammalian brains of affected individuals is that they are smooth systems have demonstrated that LIS1 interacts with tu-and largely devoid of the sulci and gyri that characterize bulin and can modulate microtubule dynamics in vitro. the normal brain. In humans, most cases of classical Genetic interactions of LIS1 with a dynein/dynactin/mi-lissencephaly result from mutations in either the genes crotubule (dynactin: a multicomponent dynein regula-LIS1 (Reiner et al., 1993) or Doublecortin (DCX), which tory complex)-mediated pathway have also been sug-is X-linked (des Portes et al. The lissencephalic brain exhibits defects in neuronal Swan et al., 1999). Together, these results suggest a migration that result in poor organization of the cortical similarity of mechanism between nuclear movement in layering and a reduced surface area and lack of cortical fungi and neuronal migration. folds, possibly due to an overall reduced number of These results place LIS1, dynein, and microtubules neurons (Reiner, 2000). LIS1 is essential for life in organ-function in a common genetic pathway. However, the isms expressing it; Drosophila and mouse embryos ho-precise nature of these interactions, as well as their mozygous for the mutated allele die as larvae or follow-cellular consequences, remains unclear. First glimpses ing implantation. While heterozygote mice are viable, as to how LIS1 might function in a neuronal context they exhibit profound defects in brain structure and were provided recently when several groups working in function. Furthermore, there is a …