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Query: UNIPROT:P06889 (Mol)
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Homozygous deletion of the Lis1 gene (Lis1(-/-)) in mouse resulted in early embryonic lethality immediately after embryo implantation by an undefined mechanism. We seek to define the nature of this demise. LIS1 (pafah1b1) is a 46 kDa protein with seven tryptophan-aspartate (WD) repeats. It docks with many proteins and has been implicated in microtubular function, cell division, intercellular transport, and nuclear and cellular motility. Combined Western and quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analyses showed that LIS1 expression from the blastocyst stage required new transcription from the embryonic genome. Consequently, the death of post-implantation embryos may not reflect the first time during development that LIS1 was required, rather, it may reflect the first time following depletion of gametic stores that its actions were essential. Following culture of blastocysts in vitro for 96 hr the inner cell mass (ICM) of null embryos were significantly smaller than ICM of wild-type siblings. Normal blastocyst outgrowths after 96-hr culture had high levels of LIS1 expression in the outer cells of developing ICM and extensive expression in trophoblast cells. Lis1(-/-) embryos had significantly smaller trophoblast nuclei than wild-type embryos. The results show that LIS1 expression is required for the continued normal development of the ICM and optimal trophoblast giant cell formation.
Mol Reprod Dev 2003 Oct
PMID:A study of the nature of embryonic lethality in LIS1-/- mice. 1295 Jan

Cortical malformations are a collection of disorders affecting brain development. Mutations in the LIS1 gene lead to a disorganized and smooth cerebral cortex caused by failure in neuronal migration. Among the clinical consequences of lissencephaly are mental retardation and intractable epilepsy. It remains unclear whether the seizures result from aberrant neuronal placement, disruption of intrinsic properties of neurons, or both. The nematode Caenorhabditis elegans offers an opportunity to study such convulsions in a simple animal with a defined nervous system. Here we show that convulsions mimicking epilepsy can be induced by a mutation in a C. elegans lis-1 allele (pnm-1), in combination with a chemical antagonist of gamma-aminobutyric acid (GABA) neurotransmitter signaling. Identical convulsions were obtained using C. elegans mutants defective in GABA transmission, whereas none of these mutants or the antagonist alone caused convulsions, indicating a threshold was exceeded in response to this combination. Crosses between pnm-1 and fluorescent marker strains designed to exclusively illuminate either the processes of GABAergic neurons or synaptic vesicles surprisingly showed no deviations in neuronal architecture. Instead, presynaptic defects in GABAergic vesicle distribution were clearly evident and could be phenocopied by RNAi directed against cytoplasmic dynein, a known LIS1 interactor. Furthermore, mutations in UNC-104, a neuronal-specific kinesin, and SNB-1, a synaptic vesicle-associated protein termed synaptobrevin, exhibit similar convulsion phenotypes following chemical induction. Taken together, these studies establish C. elegans as a system to investigate subtle cytoskeletal mechanisms regulating intrinsic neuronal activity and suggest that it may be possible to dissociate the epileptic consequences of lissencephaly from the more phenotypically overt cortical defects associated with neuronal migration.
Hum Mol Genet 2004 Sep 15
PMID:Epileptic-like convulsions associated with LIS-1 in the cytoskeletal control of neurotransmitter signaling in Caenorhabditis elegans. 1525 12

Proper human brain formation is dependent upon the integrated activity of multiple genes. Malfunctioning of key proteins results in brain developmental abnormalities. Mutation(s) in the LIS1 gene or the X-linked gene doublecortin (DCX) results in a spectrum of disorders including lissencephaly, or "smooth brain", and subcortical band heterotopia, or "doublecortex". Here, we will focus on a particular subset of missense mutations in these two genes and their effect on protein structure and function.
Cell Mol Life Sci 2005 Feb
PMID:Missense mutations resulting in type 1 lissencephaly. 1571 69

The widespread LIS1-proteins were originally identified as the target for sporadic mutations causing lissencephaly in humans. Dictyostelium LIS1 (DdLIS1) is a microtubule-associated protein exhibiting 53% identity to human LIS1. It colocalizes with dynein at isolated, microtubule-free centrosomes, suggesting that both are integral centrosomal components. Replacement of the DdLIS1 gene by the hypomorphic D327H allele or overexpression of an MBP-DdLIS1 fusion disrupted various dynein-associated functions. Microtubules lost contact with the cell cortex and were dragged behind an unusually motile centrosome. Previously, this phenotype was observed in cells overexpressing fragments of dynein or the XMAP215-homologue DdCP224. DdLIS1 was coprecipitated with DdCP224, suggesting that both act together in dynein-mediated cortical attachment of microtubules. Furthermore, DdLIS1-D327H mutants showed Golgi dispersal and reduced centrosome/nucleus association. Defects in DdLIS1 function also altered actin dynamics characterized by traveling waves of actin polymerization correlated with a reduced F-actin content. DdLIS1 could be involved in actin dynamics through Rho-GTPases, because DdLIS1 interacted directly with Rac1A in vitro. Our results show that DdLIS1 is required for maintenance of the microtubule cytoskeleton, Golgi apparatus and nucleus/centrosome association, and they suggest that LIS1-dependent alterations of actin dynamics could also contribute to defects in neuronal migration in lissencephaly patients.
Mol Biol Cell 2005 Jun
PMID:Dictyostelium LIS1 is a centrosomal protein required for microtubule/cell cortex interactions, nucleus/centrosome linkage, and actin dynamics. 1580 59

In Aspergillus nidulans, cytoplasmic dynein and NUDF/LIS1 are found at the spindle poles during mitosis, but they seem to be targeted to this location via different mechanisms. The spindle pole localization of cytoplasmic dynein requires the function of the anaphase-promoting complex (APC), whereas that of NUDF does not. Moreover, although NUDF's localization to the spindle poles does not require a fully functional dynein motor, the function of NUDF is important for cytoplasmic dynein's targeting to the spindle poles. Interestingly, a gamma-tubulin mutation, mipAR63, nearly eliminates the localization of cytoplasmic dynein to the spindle poles, but it has no apparent effect on NUDF's spindle pole localization. Live cell analysis of the mipAR63 mutant revealed a defect in chromosome separation accompanied by unscheduled spindle elongation before the completion of anaphase A, suggesting that gamma-tubulin may recruit regulatory proteins to the spindle poles for mitotic progression. In A. nidulans, dynein is not apparently required for mitotic progression. In the presence of a low amount of benomyl, a microtubule-depolymerizing agent, however, a dynein mutant diploid strain exhibits a more pronounced chromosome loss phenotype than the control, indicating that cytoplasmic dynein plays a role in chromosome segregation.
Mol Biol Cell 2005 Aug
PMID:Cytoplasmic dynein's mitotic spindle pole localization requires a functional anaphase-promoting complex, gamma-tubulin, and NUDF/LIS1 in Aspergillus nidulans. 1593 Jan 34

Recently, we have shown that a cancer causing truncation in adenomatous polyposis coli (APC) (APC(1-1450)) dominantly interferes with mitotic spindle function, suggesting APC regulates microtubule dynamics during mitosis. Here, we examine the possibility that APC mutants interfere with the function of EB1, a plus-end microtubule-binding protein that interacts with APC and is required for normal microtubule dynamics. We show that siRNA-mediated inhibition of APC, EB1, or APC and EB1 together give rise to similar defects in mitotic spindles and chromosome alignment without arresting cells in mitosis; in contrast inhibition of CLIP170 or LIS1 cause distinct spindle defects and mitotic arrest. We show that APC(1-1450) acts as a dominant negative by forming a hetero-oligomer with the full-length APC and preventing it from interacting with EB1, which is consistent with a functional relationship between APC and EB1. Live-imaging of mitotic cells expressing EB1-GFP demonstrates that APC(1-1450) compromises the dynamics of EB1-comets, increasing the frequency of EB1-GFP pausing. Together these data provide novel insight into how APC may regulate mitotic spindle function and how errors in chromosome segregation are tolerated in tumor cells.
Mol Biol Cell 2005 Oct
PMID:APC and EB1 function together in mitosis to regulate spindle dynamics and chromosome alignment. 1603 Feb 54

Regulation of cytoplasmic dynein and microtubule dynamics is crucial for both mitotic cell division and neuronal migration. NDEL1 was identified as a protein interacting with LIS1, the protein product of a gene mutated in the lissencephaly. To elucidate NDEL1 function in vivo, we generated null and hypomorphic alleles of Ndel1 in mice by targeted gene disruption. Ndel1(-/-) mice were embryonic lethal at the peri-implantation stage like null mutants of Lis1 and cytoplasmic dynein heavy chain. In addition, Ndel1(-/-) blastocysts failed to grow in culture and exhibited a cell proliferation defect in inner cell mass. Although Ndel1(+/-) mice displayed no obvious phenotypes, further reduction of NDEL1 by making null/hypomorph compound heterozygotes (Ndel1(cko/-)) resulted in histological defects consistent with mild neuronal migration defects. Double Lis1(cko/+)-Ndel1(+/-) mice or Lis1(+/-)-Ndel1(+/-) mice displayed more severe neuronal migration defects than Lis1(cko/+)-Ndel1(+/)(+) mice or Lis1(+/-)-Ndel1(+/+) mice, respectively. We demonstrated distinct abnormalities in microtubule organization and similar defects in the distribution of beta-COP-positive vesicles (to assess dynein function) between Ndel1 or Lis1-null MEFs, as well as similar neuronal migration defects in Ndel1- or Lis1-null granule cells. Rescue of these defects in mouse embryonic fibroblasts and granule cells by overexpressing LIS1, NDEL1, or NDE1 suggest that NDEL1, LIS1, and NDE1 act in a common pathway to regulate dynein but each has distinct roles in the regulation of microtubule organization and neuronal migration.
Mol Cell Biol 2005 Sep
PMID:Complete loss of Ndel1 results in neuronal migration defects and early embryonic lethality. 1610 26

LIS1 is mutated in the human neuronal migration defect lissencephaly and along with NDEL1 (formerly NUDEL) participates in the regulation of cytoplasmic dynein function during neuronal development. Targeted disruption of Ndel1 suggested that NDEL1 could have other molecular targets that regulate microtubule organization for proper neuronal migration. To further understanding the molecular mechanism of LIS1 and lissencephaly, we identified the katanin p60 microtubule-severing protein as an additional molecular target of NDEL1. We demonstrate that phosphorylation of NDEL1 by Cdk5 facilitates interaction between NDEL1 and p60, suggesting that P-NDEL1 regulates the distribution of katanin p60. Abnormal accumulation of p60 in nucleus of Ndel1 null mutants supports an essential role of NDEL1 in p60 regulation. Complete loss of NDEL1 or expression of dominant negative mutants of p60 in migrating neurons results in defective migration and elongation of nuclear-centrosomal distance. Our results suggest that NDEL1 is essential for mitotic cell division and neuronal migration not only via regulation of cytoplasmic dynein function but also by modulation of katanin p60 localization and function.
Hum Mol Genet 2005 Nov 01
PMID:Recruitment of katanin p60 by phosphorylated NDEL1, an LIS1 interacting protein, is essential for mitotic cell division and neuronal migration. 1620 47

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an infantile autosomal-recessive motor neuron disease caused by mutations in the immunoglobulin micro-binding protein 2. We investigated the potential of a spinal cord neural stem cell population isolated on the basis of aldehyde dehydrogenase (ALDH) activity to modify disease progression of nmd mice, an animal model of SMARD1. ALDH(hi)SSC(lo) stem cells are self-renewing and multipotent and when intrathecally transplanted in nmd mice generate motor neurons properly localized in the spinal cord ventral horns. Transplanted nmd animals presented delayed disease progression, sparing of motor neurons and ventral root axons and increased lifespan. To further investigate the molecular events responsible for these differences, microarray and real-time reverse transcription-polymerase chain reaction analyses of wild-type, mutated and transplanted nmd spinal cord were undertaken. We demonstrated a down-regulation of genes involved in excitatory amino acid toxicity and oxidative stress handling, as well as an up-regulation of genes related to the chromatin organization in nmd compared with wild-type mice, suggesting that they may play a role in SMARD1 pathogenesis. Spinal cord of nmd-transplanted mice expressed high transcript levels for genes related to neurogenesis such as doublecortin (DCX), LIS1 and drebrin. The presence of DCX-expressing cells in adult nmd spinal cord suggests that both exogenous and endogenous neurogeneses may contribute to the observed nmd phenotype amelioration.
Hum Mol Genet 2006 Jan 15
PMID:Transplanted ALDHhiSSClo neural stem cells generate motor neurons and delay disease progression of nmd mice, an animal model of SMARD1. 1633 14

Miller-Dieker lissencephaly, or "smooth-brain" is a debilitating genetic developmental syndrome of the cerebral cortex, and is linked to mutations in the Lis1 gene. The LIS1 protein contains a so-called LisH motif at the N terminus, followed by a coiled-coil region and a seven WD-40 repeat forming beta-propeller structure. In vivo and in vitro, LIS1 is a dimer, and the dimerization is mediated by the N-terminal fragment and is essential for the protein's biological function. The recently determined crystal structure of the murine LIS1 N-terminal fragment encompassing residues 1-86 (N-LIS1) revealed that the LisH motif forms a tightly associated homodimer with a four-helix antiparallel bundle core, while the parallel coiled-coil situated downstream is stabilized by three canonical heptad repeats. This homodimer is uniquely asymmetric because of a distinct kink in one of the helices. Because the LisH motif is widespread among many proteins, some of which are implicated in human diseases, we investigated in detail the mechanism of N-LIS1 dimerization. We found that dimerization is dependent on both the LisH motif and the residues downstream of it, including the first few turns of the helix. We also have found that the coiled-coil does not contribute to dimerization, but instead is very labile and can adopt both supercoiled and helical conformations. These observations suggest that the presence of the LisH motif alone is not sufficient for high-affinity homodimerization and that other structural elements are likely to play an important role in this large family of proteins. The observed lability of the coiled-coil fragment in LIS1 is most likely of functional importance.
J Mol Biol 2006 Mar 24
PMID:The dimerization mechanism of LIS1 and its implication for proteins containing the LisH motif. 1644 39


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