Abnormal Spindle Protein, Asp, and the Integrity of Mitotic Centrosomal Microtubule Organizing Centers

Avides, Maria do Carmo; Glover, David M.

doi:10.1126/science.283.5408.1733

Cited by 157 publications

(103 citation statements)

References 15 publications

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“…Furthermore, the mitotic centrosomal localisation of GFP-MCPH1(S) is intriguing, as it suggests that Microcephalin could co-localise with the other primary microcephaly proteins during mitosis. In contrast to the nuclear localisation generally reported for Microcephalin (Lin et al, 2005;Xu et al, 2004), all other primary microcephaly proteins, ASPM, CDK5RAP2 and CENPJ, and their Drosophila homologues (Asp, Cnn and Sas-4, respectively) are centrosomally localised (Basto et al, 2006;Bond et al, 2002;Bond et al, 2005;do Carmo Avides and Glover, 1999;Megraw et al, 1999). Therefore Drosophila MCPH1 could still act in the same biochemical pathway as other primary microcephaly orthologs.…”

Section: Discussionmentioning

confidence: 82%

Microcephalin coordinates mitosis in the syncytialDrosophilaembryo

Brunk

Vernay

Griffith

et al. 2007

Journal of Cell Science

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Microcephalin (MCPH1) is mutated in primary microcephaly, an autosomal recessive human disorder of reduced brain size. It encodes a protein with three BRCT domains that has established roles in DNA damage signalling and the cell cycle, regulating chromosome condensation. Significant adaptive evolutionary changes in primate MCPH1 sequence suggest that changes in this gene could have contributed to the evolution of the human brain. To understand the developmental role of microcephalin we have studied its function in Drosophila. We report here that Drosophila MCPH1 is cyclically localised during the cell cycle, co-localising with DNA during interphase, but not with mitotic chromosomes. mcph1 mutant flies have a maternal effect lethal phenotype, due to mitotic arrest occurring in early syncytial cell cycles. Mitotic entry is slowed from the very first mitosis in such embryos, with prolonged prophase and metaphase stages; and frequent premature separation as well as detachment of centrosomes. As a consequence, centrosome and nuclear cycles become uncoordinated, resulting in arrested embryonic development. Phenotypic similarities with abnormal spindle (asp) and centrosomin (cnn) mutants (whose human orthologues are also mutated in primary microcephaly), suggest that further studies in the Drosophila embryo may establish a common developmental and cellular pathway underlying the human primary microcephaly phenotype.

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Section: Discussionmentioning

confidence: 82%

Microcephalin coordinates mitosis in the syncytialDrosophilaembryo

Brunk

Vernay

Griffith

et al. 2007

Journal of Cell Science

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“…The most common cause of primary autosomal recessive microcephaly is mutation in the abnormal spindle-like microcephaly associated (ASPM) gene. ASPM is highly expressed in neural precursors and the protein is localized to mitotic spindle poles (Kouprina et al, 2005), and its Drosophila counterpart, Asp, is an asymmetrically localized centrosomal protein required for mitotic spindle integrity (do Carmo Avides and Glover, 1999). Similarly, knock-down of Aspm in telencephalic neuroepithelial cells causes alterations in cleavage plane orientation and leads to an increased frequency of asymmetric division (Fish et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Cell-Autonomous β-Catenin Signaling Regulates Cortical Precursor Proliferation

Woodhead¹,

Mutch²,

Olson³

et al. 2006

J. Neurosci.

207

209

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Overexpression of ␤-catenin, a protein that functions in both cell adhesion and signaling, causes expansion of the cerebral cortical precursor population and cortical surface area enlargement. Here, we find that focal elimination of ␤-catenin from cortical neural precursors in vivo causes premature neuronal differentiation. Precursors within the cerebral cortical ventricular zone exhibit robust ␤-catenin-mediated transcriptional activation, which is downregulated as cells exit the ventricular zone. Targeted inhibition of ␤-catenin signaling during embryonic development causes cortical precursor cells to prematurely exit the cell cycle, differentiate into neurons, and migrate to the cortical plate. These results show that ␤-catenin-mediated transcriptional activation functions in the decision of cortical ventricular zone precursors to proliferate or differentiate during development, and suggest that the cell-autonomous signaling activity of ␤-catenin can control the production of cortical neurons and thus regulate cerebral cortical size.

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“…A large percentage (20%) of these bipolar spindles are asymmetrical as judged by microtubule density or/and polar focalization. Mutant cells show abnormal distribution of Abnormal spindle protein (Asp), a protein that accumulates at the minus ends of microtubules (do Carmo Avides and Glover, 1999;Wakefield et al, 2001;Riparbelli et al, 2002). In wild-type prometaphases, Asp occurs as a regular staining on the side of the centrosome facing the spindle ( Figure 3B, a).…”

Section: Dgrip84 Mutant Cells Display Abnormal Microtubule Organizatimentioning

confidence: 99%

TheDrosophilaγ-Tubulin Small Complex Subunit Dgrip84 Is Required for Structural and Functional Integrity of the Spindle Apparatus

Colombié

Vérollet

Sampaio

et al. 2006

MBoC

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␥-Tubulin, a protein critical for microtubule assembly, functions within multiprotein complexes. However, little is known about the respective role of ␥-tubulin partners in metazoans. For the first time in a multicellular organism, we have investigated the function of Dgrip84, the Drosophila orthologue of the Saccharomyces cerevisiae ␥-tubulin-associated protein Spc97p. Mutant analysis shows that Dgrip84 is essential for viability. Its depletion promotes a moderate increase in the mitotic index, correlated with the appearance of monopolar or unpolarized spindles, impairment of centrosome maturation, and increase of polyploid nuclei. This in vivo study is strengthened by an RNA interference approach in cultured S2 cells. Electron microscopy analysis suggests that monopolar spindles might result from a failure of centrosome separation and an unusual microtubule assembly pathway via centriolar triplets. Moreover, we point to an involvement of Dgrip84 in the spindle checkpoint regulation and in the maintenance of interphase microtubule dynamics. Dgrip84 also seems essential for male meiosis, ensuring spindle bipolarity and correct completion of cytokinesis. These data sustain that Dgrip84 is required in some aspects of microtubule dynamics and organization both in interphase and mitosis. The nature of a minimal ␥-tubulin complex necessary for proper microtubule organization in the metazoans is discussed. INTRODUCTIONThe mechanisms of microtubule nucleation remain unclear, although it has been demonstrated that ␥-tubulin, a universal component of the microtubule-organizing centers, plays an essential role in microtubule nucleation. The molecular details of this process are still poorly understood (Oakley and Oakley, 1989;Oakley et al., 1990;Erickson and Stoffler, 1996;Gunawardane et al., 2003). In vitro, ␥-tubulin monomers enhance the assembly of ␣/␤ heterodimers and block the minus ends of microtubules (Li and Joshi, 1995;Leguy et al., 2000). However, in vivo, ␥-tubulin does not seem to act as a monomer, but rather in a variety of protein complexes (Murphy et al., 1998;Oegema et al., 1999;Fujita et al., 2002). The simplest one called ␥-tubulin small complex (␥-TuSC) has been well characterized in Saccharomyces cerevisiae , Drosophila melanogaster (Oegema et al., 1999), and vertebrates (Murphy et al., 1998). It is formed by ␥-tubulin and two associated proteins in a 2:1:1 stoichiometry Oegema et al., 1999;Murphy et al., 2001). This small complex is recruited at the inner and outer spindle plaques of S. cerevisiae spindle pole bodies (SPB) where it is responsible for microtubule nucleation Schiebel, 1997, 1998;Pereira et al., 1998). Besides ␥-TuSC, other larger ␥-tubulin-containing complexes have been described (Zheng et al., 1995;Fujita et al., 2002). One termed ␥-tubulin ring complex (␥-TuRC) has been characterized in multicellular organisms such as D. melanogaster, Xenopus laevis, and Homo sapiens (Zheng et al., 1995;Oegema et al., 1999;Murphy et al., 2001). It is assumed that the ␥-TuRC results from the associa...

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Abnormal Spindle Protein, Asp, and the Integrity of Mitotic Centrosomal Microtubule Organizing Centers

Cited by 157 publications

References 15 publications

Microcephalin coordinates mitosis in the syncytialDrosophilaembryo

Microcephalin coordinates mitosis in the syncytialDrosophilaembryo

Cell-Autonomous β-Catenin Signaling Regulates Cortical Precursor Proliferation

TheDrosophilaγ-Tubulin Small Complex Subunit Dgrip84 Is Required for Structural and Functional Integrity of the Spindle Apparatus

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