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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    • "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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    • "Depletion of three other genes by RNAi caused migration delays, namely Lis-1, Dynein (DHC64C) and NudE (Fig. 4B). Lis-1 and NudE work together with the microtubule minus end-directed motor Dynein to perform load-bearing transport [35], which is important for movement of nuclei, to organize the microtubule cytoskeleton and for cell migration in several contexts [11], [36]. It was notable how few genes were found to have a role in border cells by this approach. "
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    ABSTRACT: The environment through which cells migrate in vivo differs considerably from the in vitro environment where cell migration is often studied. In vivo many cells migrate in crowded and complex 3-dimensional tissues and may use other cells as the substratum on which they move. This includes neurons, glia and their progenitors in the brain. Here we use a Drosophila model of invasive, collective migration in a cellular environment to investigate the roles of microtubules and microtubule regulators in this type of cell movement. Border cells are of epithelial origin and have no visible microtubule organizing center (MTOC). Interestingly, microtubule plus-end growth was biased away from the leading edge. General perturbation of the microtubule cytoskeleton and analysis by live imaging showed that microtubules in both the migrating cells and the substrate cells affect movement. Also, whole-tissue and cell autonomous deletion of the microtubule regulator Stathmin had distinct effects. A screen of 67 genes encoding microtubule interacting proteins uncovered cell autonomous requirements for Lis-1, NudE and Dynein in border cell migration. Net cluster migration was decreased, with initiation of migration and formation of dominant front cell protrusion being most dramatically affected. Organization of cells within the cluster and localization of cell-cell adhesion molecules were also abnormal. Given the established role of Lis-1 in migrating neurons, this could indicate a general role of Lis-1/NudE, Dynein and microtubules, in cell-on-cell migration. Spatial regulation of cell-cell adhesion may be a common theme, consistent with observing both cell autonomous and non-autonomous requirements in both systems.
    PLoS ONE 07/2012; 7(7):e40632. DOI:10.1371/journal.pone.0040632 · 3.23 Impact Factor
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