Vallee, R. B. & Tsai, J. W. The cellular roles of the lissencephaly gene LIS1, and what they tell us about brain development. Genes Dev. 20, 1384-1393

Department of Pathology and Cell Biology, Center for Neurobiology and Behavior, Columbia University College of Physicians and Surgeons, New York, New York 10032 USA.
Genes & Development (Impact Factor: 10.8). 07/2006; 20(11):1384-93. DOI: 10.1101/gad.1417206
Source: PubMed
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    • "Dynein mutants have shown defects in organelle organization and transport and in the Spk stability (Xiang and Plamann, 2003). LIS1 is a human Mt associated protein that has been implicated in the regulation of the dynein/dynactin complex, a major Mt motor protein (Vallee and Tsai, 2006). Sporadic mutations in the human lis1 gene produce lissencephaly or 'smooth brain', a severe brain disease characterized by mislocalization of cortical neurons (Reiner et al., 1995; Izumi et al., 2007). "
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    ABSTRACT: LIS1 is a microtubule (Mt) plus-end binding protein that interacts with the dynein/dynactin complex. In humans, LIS1 is required for proper nuclear and organelle migration during cell growth. Although gene duplication is absent from Neurospora crassa, we found two paralogues of human LIS1. We named them LIS1-1 and LIS1-2 and studied their dynamics and function by fluorescent tagging. At the protein level, LIS1-1 and LIS1-2 were very similar. Although, the characteristic coiled-coil motif was not present in LIS1-2. LIS1-1-GFP and LIS1-2-GFP showed the same cellular distribution and dynamics, but LIS1-2-GFP was less abundant. Both LIS1 proteins were found in the subapical region as single fluorescent particles traveling towards the cell apex, they accumulated in the apical dome forming prominent short filament-like structures, some of which traversed the Spitzenkörper (Spk). The fluorescent structures moved exclusively in anterograde fashion along straight paths suggesting they traveled on Mts. There was no effect in the filament behavior of LIS1-1-GFP in the Δlis1-2 mutant but the dynamics of LIS1-2-GFP was affected in the Δlis1-1 mutant. Microtubular integrity and the dynein-dynactin complex were necessary for the formation of filament-like structures of LIS1-1-GFP in the subapical and apical regions; however, conventional kinesin (KIN-1) was not. Deletion mutants showed that the lack of lis1-1 decreased cell growth by ∼75%; however, the lack of lis1-2 had no effect on growth. A Δlis1-1;Δlis1-2 double mutant showed slower growth than either single mutant. Conidia production was reduced but branching rate increased in Δlis1-1 and the Δlis1-1;Δlis1-2 double mutants. The absence of LIS1-1 had a strong effect on Mt organization and dynamics and indirectly affected nuclear and mitochondrial distribution. The absence of LIS1-1 filaments in dynein mutants (ropy mutants) or in benomyl treated hyphae indicates the strong association between this protein and the regulation of the dynein-dynactin complex and Mt organization. LIS1-1 and LIS1-2 had a high amino acid homology, nevertheless, the absence of the coiled-coil motif in LIS1-2 suggests that its function or regulation may be distinct from that of LIS1-1. Copyright © 2015. Published by Elsevier Inc.
    Fungal Genetics and Biology 07/2015; 82. DOI:10.1016/j.fgb.2015.07.009 · 2.59 Impact Factor
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    • "These data imply that KASH5 is an adaptor for cytoplasmic dynein. Additional coIP experiments revealed associations with dynein IC and p150 Glued as well as with LIS1, another dynein regulator (Fig. 2 F; Vallee and Tsai, 2006). We next prepared a series of KASH5 deletion mutants (Fig. 2 E). "
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    ABSTRACT: Chromosome pairing is an essential meiotic event that ensures faithful haploidization and recombination of the genome. Pairing of homologous chromosomes is facilitated by telomere-led chromosome movements and formation of a meiotic bouquet, where telomeres cluster to one pole of the nucleus. In metazoans, telomere clustering is dynein and microtubule dependent and requires Sun1, an inner nuclear membrane protein. Here we provide a functional analysis of KASH5, a mammalian dynein-binding protein of the outer nuclear membrane that forms a meiotic complex with Sun1. This protein is related to zebrafish futile cycle (Fue), a nuclear envelope (NE) constituent required for pronuclear migration. Mice deficient in this Fue homologue are infertile. Males display meiotic arrest in which pairing of homologous chromosomes fails. These findings demonstrate that telomere attachment to the NE is insufficient to promote pairing and that telomere attachment sites must be coupled to cytoplasmic dynein and the microtubule system to ensure meiotic progression.
    The Journal of Cell Biology 09/2013; 202(7). DOI:10.1083/jcb.201304004 · 9.83 Impact Factor
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    • "Lis1 is widely expressed in postnatal and adult brain, including hippocampus and barrel cortex, and enriched in synaptosomal fractions (McKenney et al, 2010; Niethammer et al, 2000). While the role of Lis1 during neuronal proliferation and migration has been comprehensively studied (Vallee & Tsai, 2006), its role in post-migrational neurons remains largely unknown. Previous electrophysiological study of Lis1 þ/À neurons showed over-excitation of excitatory hippocampal circuits as a consequence of increased presynaptic vesicle numbers per terminal (Greenwood et al, 2009). "
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    ABSTRACT: LIS1 (PAFAH1B1) mutation can impair neuronal migration, causing lissencephaly in humans. LIS1 loss is associated with dynein protein motor dysfunction, and disrupts the actin cytoskeleton through disregulated RhoGTPases. Recently, LIS1 was implicated as an important protein-network interaction node with high-risk autism spectrum disorder genes expressed in the synapse. How LIS1 might participate in this disorder has not been investigated. We examined the role of LIS1 in synaptogenesis of post-migrational neurons and social behaviour in mice. Two-photon imaging of actin-rich dendritic filopodia and spines in vivo showed significant reductions in elimination and turnover rates of dendritic protrusions of layer V pyramidal neurons in adolescent Lis1+/- mice. Lis1+/- filopodia on immature hippocampal neurons in vitro exhibited reduced density, length and RhoA dependent impaired dynamics compared to Lis1+/+ . Moreover, Lis1+/- adolescent mice exhibited deficits in social interaction. Lis1 inactivation restricted to the postnatal hippocampus resulted in similar deficits in dendritic protrusion density and social interactions. Thus, LIS1 plays prominently in dendritic filopodia dynamics and spine turnover implicating reduced dendritic spine plasticity as contributing to developmental autistic-like behaviour.
    EMBO Molecular Medicine 04/2013; 5(4). DOI:10.1002/emmm.201202106 · 8.67 Impact Factor
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