Higgins, Julie; Midgley, Carol A.; 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; MorrisonBond, Ewan E. and Bond, Jacquelyn
PDF (Accepted Manuscript)
- Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
|DOI (Digital Object Identifier) Link:||https://doi.org/10.1186/1471-2121-11-85|
|Google Scholar:||Look up in Google Scholar|
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.
|Item Type:||Journal Article|
|Copyright Holders:||2010 The Authors|
|Academic Unit/Department:||Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Faculty of Science, Technology, Engineering and Mathematics (STEM)
|Interdisciplinary Research Centre:||Biomedical Research Network (BRN)|
|Depositing User:||Carol Midgley|
|Date Deposited:||04 Nov 2010 09:41|
|Last Modified:||05 Oct 2016 21:33|
|Share this page:|
Download history for this item
These details should be considered as only a guide to the number of downloads performed manually. Algorithmic methods have been applied in an attempt to remove automated downloads from the displayed statistics but no guarantee can be made as to the accuracy of the figures.