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WDR62 is associated with the spindle pole and is mutated in human microcephaly

Nature Genetics volume 42, pages 1010–1014 (2010)Cite this article

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Abstract

Autosomal recessive primary microcephaly (MCPH) is a disorder of neurodevelopment resulting in a small brain1,2. We identified WDR62 as the second most common cause of MCPH after finding homozygous missense and frame-shifting mutations in seven MCPH families. In human cell lines, we found that WDR62 is a spindle pole protein, as are ASPM and STIL, the MCPH7 and MCHP7 proteins3,4,5. Mutant WDR62 proteins failed to localize to the mitotic spindle pole. In human and mouse embryonic brain, we found that WDR62 expression was restricted to neural precursors undergoing mitosis. These data lend support to the hypothesis that the exquisite control of the cleavage furrow orientation in mammalian neural precursor cell mitosis, controlled in great part by the centrosomes and spindle poles, is critical both in causing MCPH when perturbed and, when modulated, generating the evolutionarily enlarged human brain6,7,8,9.

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Figure 1: A summary of the linkage strategy used to define the MCPH2 region and mutations found in WDR62 in MCPH2 families.
Figure 2: Subcellular localization of WDR62 throughout the cell cycle.
Figure 3: Overexpression of WDR62-GFP wild type and c.1313G>A (p.Arg438His) mutant constructs in HeLa cells.
Figure 4: Endogenous expression pattern of WDR62 in human and mouse embryonic brain.
Figure 5: Wdr62 expression in newborn, newly arrived cortical neurons in the developing cerebral cortex and brain imaging from two individuals with WDR62 mutations.

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References

  1. Mochida, G.H. & Walsh, C.A. Genetic basis of developmental malformations of the cerebral cortex. Arch. Neurol. 61, 637–640 (2004).

    Google Scholar 

  2. Woods, C.G., Bond, J. & Enard, W. Autosomal recessive primary microcephaly (MCPH): a review of clinical, molecular, and evolutionary findings. Am. J. Hum. Genet. 76, 717–728 (2005).

    Google Scholar 

  3. Bond, J. et al. ASPM is a major determinant of cerebral cortical size. Nat. Genet. 32, 316–320 (2002).

    Google Scholar 

  4. Pfaff, K.L. et al. The zebra fish cassiopeia mutant reveals that SIL is required for mitotic spindle organization. Mol. Cell. Biol. 27, 5887–5897 (2007).

    Google Scholar 

  5. Bond, J. & Woods, C.G. Cytoskeletal genes regulating brain size. Curr. Opin. Cell Biol. 18, 95–101 (2006).

    Google Scholar 

  6. Fish, J.L., Kosodo, Y., Enard, W., Pääbo, S. & Huttner, W.B. Aspm specifically maintains symmetric proliferative divisions of neuroepithelial cells. Proc. Natl. Acad. Sci. USA 103, 10438–10443 (2006).

    Google Scholar 

  7. Fish, J.L., Dehay, C., Kennedy, H. & Huttner, W.B. Making bigger brains–the evolution of neural-progenitor-cell division. J. Cell Sci. 121, 2783–2793 (2008).

    Google Scholar 

  8. Marthiens, V. & ffrench-Constant, C. Adherens junction domains are split by asymmetric division of embryonic neural stem cells. EMBO Rep. 10, 515–520 (2009).

    Google Scholar 

  9. Thornton, G.K. & Woods, C.G. Primary microcephaly: do all roads lead to Rome? Trends Genet. 25, 501–510 (2009).

    Google Scholar 

  10. Roberts, E. et al. The second locus for autosomal recessive primary microcephaly (MCPH2) maps to chromosome 19q13.1–13.2. Eur. J. Hum. Genet. 7, 815–820 (1999).

    Google Scholar 

  11. Jackson, A.P. et al. Identification of microcephalin, a protein implicated in determining the size of the human brain. Am. J. Hum. Genet. 71, 136–142 (2002).

    Google Scholar 

  12. Bond, J. et al. A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size. Nat. Genet. 37, 353–355 (2005).

    Google Scholar 

  13. Kumar, A., Girimaji, S.C., Duvvari, M.R. & Blanton, S.H. Mutations in STIL, encoding a pericentriolar and centrosomal protein, cause primary microcephaly. Am. J. Hum. Genet. 84, 286–290 (2009).

    Google Scholar 

  14. Passemard, S. et al. Primary autosomal recessive microcephaly. GeneReviews. (University of Washington, Seattle, WA, 2009) <http://www.ncbi.nlm.nih.gov/pubmed/20301772>.

  15. Roberts, E. et al. Autosomal recessive primary microcephaly: an analysis of locus heterogeneity and phenotypic variation. J. Med. Genet. 39, 718–721 (2002).

    Google Scholar 

  16. Mardis, E.R. New strategies and emerging technologies for massively parallel sequencing: applications in medical research. Genome Med. 1, 40 (2009).

    Google Scholar 

  17. Field, M. et al. Mutations in the BRWD3 gene cause X–linked mental retardation associated with macrocephaly. Am. J. Hum. Genet. 81, 367–374 (2007).

    Google Scholar 

  18. Nousiainen, M., Silljé, H.H., Sauer, G., Nigg, E.A. & Körner, R. Phosphoproteome analysis of the human mitotic spindle. Proc. Natl. Acad. Sci. USA 103, 5391–5396 (2006).

    Google Scholar 

  19. Malik, R. et al. Quantitative analysis of the human spindle phosphoproteome at distinct mitotic stages. J. Proteome Res. 8, 4553–4563 (2009).

    Google Scholar 

  20. do Carmo Avides, M., Tavares, A. & Glover, D.M. Polo kinase and Asp are needed to promote the mitotic organizing activity of centrosomes. Nat. Cell Biol. 3, 421–424 (2001).

    Google Scholar 

  21. Caspi, M. et al. LIS1 missense mutations: variable phenotypes result from unpredictable alterations in biochemical and cellular properties. J. Biol. Chem. 278, 38740–38748 (2003).

    Google Scholar 

  22. Gardette, R., Courtois, M. & Bisconte, J.C. Prenatal development of mouse central nervous structures: time of neuron origin and gradients of neuronal production. A radioautographic study. J. Hirnforsch. 23, 415–431 (1982).

    Google Scholar 

  23. Uylings, H.B. Development of the cerebral cortex in rodents and man. Eur. J. Morphol. 38, 309–312 (2000).

    Google Scholar 

  24. Bystron, I., Blakemore, C. & Rakic, P. Development of the human cerebral cortex: Boulder Committee revisited. Nat. Rev. Neurosci. 9, 110–122 (2008).

    Google Scholar 

  25. Attardo, A., Calegari, F., Haubensak, W., Wilsch-Brauninger, W.M. & Huttner, W.B. Live imaging at the onset of cortical neurogenesis reveals differential appearance of the neuronal phenotype in apical versus basal progenitor progeny. PLoS ONE 3, e2388 (2008).

    Google Scholar 

  26. Noctor, S.C., Martinez-Cerdeno, V. & Kriegstein, A.R. Distinct behaviors of neural stem and progenitor cells underlie cortical neurogenesis. J. Comp. Neurol. 508, 28–44 (2008).

    Google Scholar 

  27. O'Rahilly, R. & Müller, F. Developmental Stages in Human Embryos: Revised and New Measurements. Cells Tissues Organs 192, 73–84 (2010).

    Google Scholar 

  28. Bilgüvar, K. et al. Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature. published online, doi:10.1038/nature09327 (22 August 2010).

  29. Barr, F.A. & Gruneberg, U. Cytokinesis: placing and making the final cut. Cell 131, 847–860 (2007).

    Google Scholar 

  30. Barr, A.R., Kilmartin, J.V. & Gergely, F. CDK5RAP2 functions in centrosome to spindle pole attachment and DNA damage response. J. Cell Biol. 189, 23–39 (2010).

    Google Scholar 

  31. Götz, M. & Huttner, W.B. The cell biology of neurogenesis. Nat. Rev. Mol. Cell Biol. 6, 777–788 (2005).

    Google Scholar 

  32. Kosodo, Y. et al. Asymmetric distribution of the apical plasma membrane during neurogenic divisions of mammalian neuroepithelial cells. EMBO J. 23, 2314–2324 (2004).

    Google Scholar 

Download references

Acknowledgements

The authors would like to thank the research families for their participation in this project and the Wellcome Trust, Medical Research Council, Action Research and the Higher Education Commission of Pakistan for funding (to A.K.N., M.K., O.P.C., J.J.C., G.T. and E.R.). J.D. was supported by the Belgian Kids' Fund. M.A. was supported by grants from the Fonds Erasme and the Belgian Fonds de la Recherche Scientifique Médicale (FRSM). We thank S. Strollo for expert technical assistance. We thank the Medical Research Council (MRC)-Wellcome Trust Human Developmental Biology Resource (HDBR), Newcastle for providing the human tissue for the expression studies.

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Author notes

  1. Adeline K Nicholas, Maryam Khurshid and Julie Désir: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK

    Adeline K Nicholas, Maryam Khurshid, Ofélia P Carvalho, James J Cox, Gemma Thornton & C Geoffrey Woods

  2. Department of Medical Genetics, Hôpital Erasme and Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université libre de Bruxelles (IRIBHM), ULB, Brussels, Belgium

    Julie Désir & Marc Abramowicz

  3. Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan

    Rizwana Kausar, Muhammad Ansar & Wasim Ahmad

  4. Department of Genetics, Robert Debré University Hospital, Paris, France

    Alain Verloes & Sandrine Passemard

  5. Department of Child Neurology, Assistance publique-Hôpitaux de Paris (AP-HP) Robert Debré University Hospital, Paris, France

    Sandrine Passemard

  6. University of Liège Medical School and Department of Pediatrics, La Citadelle University Hospital, Liège, Belgium

    Jean-Paul Misson

  7. Institute of Human Genetics, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, UK

    Susan Lindsay

  8. Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK

    Fanni Gergely

  9. Department of Human Genetics, University of Chicago, Chicago, Illinois, USA

    William B Dobyns

  10. Microcephaly and Neurogenesis research group, Leeds Institute of Molecular Medicine, St. James's University Hospital, Leeds, UK

    Emma Roberts

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  1. Adeline K Nicholas
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Contributions

The following authors contributed to the design of the study: A.K.N., M.K., J.J.C., F.G., E.R., M. Abramowicz and C.G.W. The following authors generated experimental data: A.K.N., M.K., J.D., O.P.C., G.T., R.K., M. Ansar, F.G., W.B.D., E.R. and C.G.W. Reagents were contributed by R.K., M. Abramowicz, W.A., A.L., S.P., J.-P.M., S.L., M. Abramowicz and C.G.W. The paper was written by A.K.N., M.K., O.P.C., J.J.C., W.A., S.L., F.G., W.B.D. and C.G.W.

Corresponding authors

Correspondence to Marc Abramowicz or C Geoffrey Woods.

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The authors declare no competing financial interests.

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Supplementary Table 1 and Supplementary Figures 1–7 (PDF 796 kb)

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Nicholas, A., Khurshid, M., Désir, J. et al. WDR62 is associated with the spindle pole and is mutated in human microcephaly. Nat Genet 42, 1010–1014 (2010). https://doi.org/10.1038/ng.682

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