Live Imaging of<i>Drosophila</i>Brain Neuroblasts Reveals a Role for Lis1/Dynactin in Spindle Assembly and Mitotic Checkpoint Control

Siller, Karsten H.; Serr, Madeline; Steward, Ruth; Hays, Tom S; Doe, Chris Q.

doi:10.1091/mbc.e05-04-0338

Cited by 120 publications

(150 citation statements)

References 69 publications

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“…1j--m; Supplementary Fig. 1) Lis1 enhances Dynein--mediated minus end--directed transport along microtubules, and previous characterization of tagged Lis1 revealed that this marker is transported towards microtubule minus ends during mitosis and meiosis 24,25 . We found that dendritic localization of tagged Lis1 24,25 also differed between class I and IV neurons, and was regulated by ab.…”

Section: Neuron Class--specific Arrangements Of the Microtubule Arraymentioning

confidence: 73%

Centrosomin represses dendrite branching by orienting microtubule nucleation

et al. 2015

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Section: Neuron Class--specific Arrangements Of the Microtubule Arraymentioning

confidence: 73%

Centrosomin represses dendrite branching by orienting microtubule nucleation

et al. 2015

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“…Freshly hatched WT pins P62 and G␣i P8 zygotic mutant larvae were aged for 96-120 h at 25°C and prepared for immunofluorescent antibody labeling as described previously, with the modification that 5% normal goat serum was added to the larval blocking and primary antibody solutions (32). Primary antibodies were rat anti-Pins [#2, 1:500 (9)], rabbit anti-G␣i (1:500; raised against peptide, amino acids 327-355), rabbit anti-Insc (1:1,000; W. Chia), rabbit anti-Mud (raised against amino acids 375-549; 1:2,000; H. Nash), mouse anti-␣-tubulin (1:2,000; DM1A, Sigma), and mouse-anti-HA (1:1,000; Covance).…”

Section: Methodsmentioning

confidence: 99%

“…32. Brains were imaged by using a Bio-Rad Radiance 2100 laser scanning confocal microscope equipped with a ϫ60 1.4-N.A.…”

Section: Analysis Of Spindle Orientation In Fixed and Live Larval Neumentioning

confidence: 99%

Gαi generates multiple Pins activation states to link cortical polarity and spindle orientation in Drosophila neuroblasts

Nipper

Siller

Smith

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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108

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Drosophila neuroblasts divide asymmetrically by aligning their mitotic spindle with cortical cell polarity to generate distinct sibling cell types. Neuroblasts asymmetrically localize G␣i, Pins, and Mud proteins; Pins/G␣i direct cortical polarity, whereas Mud is required for spindle orientation. It is currently unknown how G␣i-Pins-Mud binding is regulated to link cortical polarity with spindle orientation. Here, we show that Pins forms a ''closed'' state via intramolecular GoLoco-tetratricopeptide repeat (TPR) interactions, which regulate Mud binding. Biochemical, genetic, and live imaging experiments show that G␣i binds to the first of three Pins GoLoco motifs to recruit Pins to the apical cortex without ''opening'' Pins or recruiting Mud. However, G␣i and Mud bind cooperatively to the Pins GoLocos 2/3 and tetratricopeptide repeat domains, respectively, thereby restricting Pins-Mud interaction to the apical cortex and fixing spindle orientation. We conclude that Pins has multiple activity states that generate cortical polarity and link it with mitotic spindle orientation.cell polarity ͉ cell signaling ͉ differentiation ͉ protein-protein interactions I n complex, multicellular organisms, differentiated cell types are needed to perform diverse functions. One common mechanism for cellular differentiation is asymmetric cell division, in which the mitotic spindle is aligned with the cell polarity axis to generate molecularly distinct sibling cells (1-4). Asymmetric divisions have been proposed to regulate stem cell pool size during development, adult tissue homeostasis, and the uncontrolled proliferation observed in cancer (5). Thus, understanding how the mitotic spindle is coupled to the cell polarity axis is relevant to stem cell and cancer biology. Here, we investigate this question in Drosophila neuroblasts, a model system for studying asymmetric cell division.Drosophila neuroblasts are stem cell-like progenitors that divide asymmetrically to produce a larger self-renewing neuroblast and a smaller ganglion mother cell (GMC) that differentiates into neurons or glia (3). Mitotic neuroblasts segregate factors that promote neuroblast self-renewal to their apical cortex and differentiation factors to their basal cortex. Precise alignment of the mitotic spindle with the neuroblast apical/basal polarity is required for asymmetric cell division and proper brain development: spindle misalignment leads to symmetric cell divisions that expand the neuroblast population and brain size (6-8).

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“…Faulkner et al 165 observed that LIS1 expression levels correlate with the length of the cell cycle. In mammals, Drosophila and Caenorhabditis elegans LIS1, NDEL1 and NDE1 are all required for formation of the mitotic spindle, 165,166 while LIS1 and NDEL1 are also implicated in checkpoint control of the cell cycle. 167 It is therefore possible that these proteins influence cortical development by modulating neuronal proliferation in the ventricular zone, 156 as well as by regulating migration of newborn neurons from the ventricular zone to the cortical plate.…”

Section: Lis1 Ndel1 Nde1 and Disc1mentioning

confidence: 99%

The DISC locus in psychiatric illness

et al. 2007

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The DISC locus is located at the breakpoint of a balanced t(1;11) chromosomal translocation in a large and unique Scottish family. This translocation segregates in a highly statistically significant manner with a broad diagnosis of psychiatric illness, including schizophrenia, bipolar disorder and major depression, as well as with a narrow diagnosis of schizophrenia alone. Two novel genes were identified at this locus and due to the high prevalence of schizophrenia in this family, they were named Disrupted-in-Schizophrenia-1 (DISC1) and Disrupted-in-Schizophrenia-2 (DISC2). DISC1 encodes a novel multifunctional scaffold protein, whereas DISC2 is a putative noncoding RNA gene antisense to DISC1. A number of independent genetic linkage and association studies in diverse populations support the original linkage findings in the Scottish family and genetic evidence now implicates the DISC locus in susceptibility to schizophrenia, schizoaffective disorder, bipolar disorder and major depression as well as various cognitive traits. Despite this, with the exception of the t(1;11) translocation, robust evidence for a functional variant(s) is still lacking and genetic heterogeneity is likely. Of the two genes identified at this locus, DISC1 has been prioritized as the most probable candidate susceptibility gene for psychiatric illness, as its protein sequence is directly disrupted by the translocation. Much research has been undertaken in recent years to elucidate the biological functions of the DISC1 protein and to further our understanding of how it contributes to the pathogenesis of schizophrenia. These data are the main subject of this review; however, the potential involvement of DISC2 in the pathogenesis of psychiatric illness is also discussed. A detailed picture of DISC1 function is now emerging, which encompasses roles in neurodevelopment, cytoskeletal function and cAMP signalling, and several DISC1 interactors have also been defined as independent genetic susceptibility factors for psychiatric illness. DISC1 is a hub protein in a multidimensional risk pathway for major mental illness, and studies of this pathway are opening up opportunities for a better understanding of causality and possible mechanisms of intervention. Molecular Psychiatry (2008) 13, 36-64; doi:10.1038/sj.mp.4002106; published online 2 October 2007 Keywords: schizophrenia; bipolar disorder; depression; DISC1; DISC2; mouse models Genetics of DISC1 discoverySt Clair et al. 1 first reported a Scottish family with a high loading of major mental illness, which cosegregates with a t(1;11) translocation. Long-term follow-up of this family over a period of 30 years has reported 87 family members, of whom 37 carry the translocation. 2 Of 29 individuals carrying the translocation, for whom psychiatric assessment was possible, 7 have a diagnosis of schizophrenia, 1 has a diagnosis of bipolar disorder and 10 cases of recurrent major depression were also reported. 2 Thus, 18 of 29 translocation carriers are diagnosed with major mental illness whereas none of...

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Live Imaging ofDrosophilaBrain Neuroblasts Reveals a Role for Lis1/Dynactin in Spindle Assembly and Mitotic Checkpoint Control

Cited by 120 publications

References 69 publications

Centrosomin represses dendrite branching by orienting microtubule nucleation

Centrosomin represses dendrite branching by orienting microtubule nucleation

Gαi generates multiple Pins activation states to link cortical polarity and spindle orientation in Drosophila neuroblasts

The DISC locus in psychiatric illness

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