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
Abstract
Abstract
Background
Mutations in the A bnormal Sp indle M icrocephaly 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.
Publisher
Springer Science and Business Media LLC
Reference51 articles.
1. Rakic P: Neuronal migration and contact guidance in the primate telencephalon. Postgrad Med J. 1978, 54: 25-40.
2. Lu B, Jan L, Jan YN: Control of cell divisions in the central nervous system: symmetry and asymmetry. Ann Rev Neurosci. 2000, 23: 531-556. 10.1146/annurev.neuro.23.1.531.
3. Chenn A, McConnell SK: Cleavage orientation and the asymmetric inheritance of Notch1 immunoreactivity in mammalian neurogenesis. Cell. 1995, 82: 631-641. 10.1016/0092-8674(95)90035-7.
4. Aicardi J: Malformations of the central nervous system. Diseases of the nervous system in childhood. 1998, Mac Keith, London, 90-91. 2
5. Bond J, Roberts E, Mochida GH, Hampshire DJ, Scott S, Askham JM, Springell K, Mahadevan M, Crow YJ, Markham AF, Walsh CA, Woods CG: ASPM is a major determinant of cerebral cortical size. Nat Genet. 2002, 32: 316-320. 10.1038/ng995.
Cited by
102 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献