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Human ASPM participates in spindle organisation, spindle orientation and cytokinesis
BACKGROUND: Mutations in the Abnormal Spindle Microcephaly related gene (ASPM) are the commonest cause of autosomal recessive primary microcephaly (MCPH) a disorder characterised by a small brain and associated mental retardation. ASPM encodes a mitotic spindle pole associated protein. It is suggest...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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BioMed Central
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2988714/ https://www.ncbi.nlm.nih.gov/pubmed/21044324 http://dx.doi.org/10.1186/1471-2121-11-85 |
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author | Higgins, Julie Midgley, Carol Bergh, Anna-Maria Bell, Sandra M Askham, Jonathan M Roberts, Emma Binns, Ruth K Sharif, Saghira M Bennett, Christopher Glover, David M Woods, C Geoffrey Morrison, Ewan E Bond, Jacquelyn |
author_facet | Higgins, Julie Midgley, Carol Bergh, Anna-Maria Bell, Sandra M Askham, Jonathan M Roberts, Emma Binns, Ruth K Sharif, Saghira M Bennett, Christopher Glover, David M Woods, C Geoffrey Morrison, Ewan E Bond, Jacquelyn |
author_sort | Higgins, Julie |
collection | PubMed |
description | BACKGROUND: Mutations in the Abnormal Spindle Microcephaly related gene (ASPM) are the commonest cause of autosomal recessive primary microcephaly (MCPH) a disorder characterised by a small brain and associated mental retardation. ASPM encodes a mitotic spindle pole associated protein. It is suggested that the MCPH phenotype arises from proliferation defects in neural progenitor cells (NPC). RESULTS: We show that ASPM is a microtubule minus end-associated protein that is recruited in a microtubule-dependent manner to the pericentriolar matrix (PCM) at the spindle poles during mitosis. ASPM siRNA reduces ASPM protein at the spindle poles in cultured U2OS cells and severely perturbs a number of aspects of mitosis, including the orientation of the mitotic spindle, the main determinant of developmental asymmetrical cell division. The majority of ASPM depleted mitotic cells fail to complete cytokinesis. In MCPH patient fibroblasts we show that a pathogenic ASPM splice site mutation results in the expression of a novel variant protein lacking a tripeptide motif, a minimal alteration that correlates with a dramatic decrease in ASPM spindle pole localisation. Moreover, expression of dominant-negative ASPM C-terminal fragments cause severe spindle assembly defects and cytokinesis failure in cultured cells. CONCLUSIONS: These observations indicate that ASPM participates in spindle organisation, spindle positioning and cytokinesis in all dividing cells and that the extreme C-terminus of the protein is required for ASPM localisation and function. Our data supports the hypothesis that the MCPH phenotype caused by ASPM mutation is a consequence of mitotic aberrations during neurogenesis. We propose the effects of ASPM mutation are tolerated in somatic cells but have profound consequences for the symmetrical division of NPCs, due to the unusual morphology of these cells. This antagonises the early expansion of the progenitor pool that underpins cortical neurogenesis, causing the MCPH phenotype. |
format | Text |
id | pubmed-2988714 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-29887142010-11-20 Human ASPM participates in spindle organisation, spindle orientation and cytokinesis Higgins, Julie Midgley, Carol Bergh, Anna-Maria Bell, Sandra M Askham, Jonathan M Roberts, Emma Binns, Ruth K Sharif, Saghira M Bennett, Christopher Glover, David M Woods, C Geoffrey Morrison, Ewan E Bond, Jacquelyn BMC Cell Biol Research Article BACKGROUND: Mutations in the Abnormal Spindle Microcephaly related gene (ASPM) are the commonest cause of autosomal recessive primary microcephaly (MCPH) a disorder characterised by a small brain and associated mental retardation. ASPM encodes a mitotic spindle pole associated protein. It is suggested that the MCPH phenotype arises from proliferation defects in neural progenitor cells (NPC). RESULTS: We show that ASPM is a microtubule minus end-associated protein that is recruited in a microtubule-dependent manner to the pericentriolar matrix (PCM) at the spindle poles during mitosis. ASPM siRNA reduces ASPM protein at the spindle poles in cultured U2OS cells and severely perturbs a number of aspects of mitosis, including the orientation of the mitotic spindle, the main determinant of developmental asymmetrical cell division. The majority of ASPM depleted mitotic cells fail to complete cytokinesis. In MCPH patient fibroblasts we show that a pathogenic ASPM splice site mutation results in the expression of a novel variant protein lacking a tripeptide motif, a minimal alteration that correlates with a dramatic decrease in ASPM spindle pole localisation. Moreover, expression of dominant-negative ASPM C-terminal fragments cause severe spindle assembly defects and cytokinesis failure in cultured cells. CONCLUSIONS: These observations indicate that ASPM participates in spindle organisation, spindle positioning and cytokinesis in all dividing cells and that the extreme C-terminus of the protein is required for ASPM localisation and function. Our data supports the hypothesis that the MCPH phenotype caused by ASPM mutation is a consequence of mitotic aberrations during neurogenesis. We propose the effects of ASPM mutation are tolerated in somatic cells but have profound consequences for the symmetrical division of NPCs, due to the unusual morphology of these cells. This antagonises the early expansion of the progenitor pool that underpins cortical neurogenesis, causing the MCPH phenotype. BioMed Central 2010-11-02 /pmc/articles/PMC2988714/ /pubmed/21044324 http://dx.doi.org/10.1186/1471-2121-11-85 Text en Copyright ©2010 Higgins et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Higgins, Julie Midgley, Carol Bergh, Anna-Maria Bell, Sandra M Askham, Jonathan M Roberts, Emma Binns, Ruth K Sharif, Saghira M Bennett, Christopher Glover, David M Woods, C Geoffrey Morrison, Ewan E Bond, Jacquelyn Human ASPM participates in spindle organisation, spindle orientation and cytokinesis |
title | Human ASPM participates in spindle organisation, spindle orientation and cytokinesis |
title_full | Human ASPM participates in spindle organisation, spindle orientation and cytokinesis |
title_fullStr | Human ASPM participates in spindle organisation, spindle orientation and cytokinesis |
title_full_unstemmed | Human ASPM participates in spindle organisation, spindle orientation and cytokinesis |
title_short | Human ASPM participates in spindle organisation, spindle orientation and cytokinesis |
title_sort | human aspm participates in spindle organisation, spindle orientation and cytokinesis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2988714/ https://www.ncbi.nlm.nih.gov/pubmed/21044324 http://dx.doi.org/10.1186/1471-2121-11-85 |
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