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ASPM is a major determinant of cerebral cortical size

Nature Genetics volume 32, pages 316–320 (2002)Cite this article

Abstract

One of the most notable trends in mammalian evolution is the massive increase in size of the cerebral cortex, especially in primates. Humans with autosomal recessive primary microcephaly (MCPH) show a small but otherwise grossly normal cerebral cortex associated with mild to moderate mental retardation1,2,3,4. Genes linked to this condition offer potential insights into the development and evolution of the cerebral cortex. Here we show that the most common cause of MCPH is homozygous mutation of ASPM, the human ortholog of the Drosophila melanogaster abnormal spindle gene (asp)5, which is essential for normal mitotic spindle function in embryonic neuroblasts6. The mouse gene Aspm is expressed specifically in the primary sites of prenatal cerebral cortical neurogenesis. Notably, the predicted ASPM proteins encode systematically larger numbers of repeated 'IQ' domains between flies, mice and humans, with the predominant difference between Aspm and ASPM being a single large insertion coding for IQ domains. Our results and evolutionary considerations suggest that brain size is controlled in part through modulation of mitotic spindle activity in neuronal progenitor cells.

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Figure 1: Magnetic resonance images of brains of individuals with an MCPH5 mutation.
Figure 2: Overview of the mapping of the MCPH5 locus and identification of ASPM.
Figure 3: Mutations in ASPM.
Figure 4: Genomic structure of ASPM; phylogenetic comparison of the primary structure of asp, Aspm and ASPM; and northern-blot analysis.
Figure 5: Expression of Aspm in developing mouse brain shown by hybridization to antisense probe.

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Acknowledgements

E.R., K.S., S.S. and C.G.W. are supported by The Wellcome Trust Research Leave Fellowship for Clinical Academics; J.B. and D.J.H. were supported by the West Riding Medical Research Trust Fund of the University of Leeds; G.H.M. is a Howard Hughes Medical Institute Physician post-doctoral fellow; and C.A.W. is supported by US National Institute of Neurological Disorders and Stroke and the March of Dimes. We thank U. Berger for help with the in situ hybridization; K.S. Krishnamoorthy, P.E. Grant and J.A.Guthrie for help with MRI images; and R.S. Hill for help with electronic analysis of candidate genes.

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  1. Jacquelyn Bond and Emma Roberts: These authors contributed equally to this work.

Authors and Affiliations

  1. Molecular Medicine Unit, University of Leeds, St. James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK

    Jacquelyn Bond, Emma Roberts, Daniel J. Hampshire, Sheila Scott, Jonathan M. Askham, Kelly Springell, Meera Mahadevan, Alexander F. Markham & C. Geoffrey Woods

  2. Division of Neurogenetics, Department of Neurology, Harvard Medical School, Howard Hughes Medical Institute, Beth Israel Deaconess Medical Center, Harvard Institute of Medicine, Boston, Massachusetts, USA

    Ganesh H. Mochida & Christopher A. Walsh

  3. Department of Neurology, Pediatric Neurology Unit, Massachusetts General Hospital, Boston, Massachusetts, USA

    Ganesh H. Mochida

  4. Department of Clinical Genetics, St. James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK

    Yanick J. Crow & C. Geoffrey Woods

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Correspondence to C. Geoffrey Woods.

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Bond, J., Roberts, E., Mochida, G. et al. ASPM is a major determinant of cerebral cortical size. Nat Genet 32, 316–320 (2002). https://doi.org/10.1038/ng995

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