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Mutations in genes encoding the cadherin receptor-ligand pair DCHS1 and FAT4 disrupt cerebral cortical development

Nature Genetics volume 45, pages 1300–1308 (2013)Cite this article

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Abstract

The regulated proliferation and differentiation of neural stem cells before the generation and migration of neurons in the cerebral cortex are central aspects of mammalian development. Periventricular neuronal heterotopia, a specific form of mislocalization of cortical neurons, can arise from neuronal progenitors that fail to negotiate aspects of these developmental processes. Here we show that mutations in genes encoding the receptor-ligand cadherin pair DCHS1 and FAT4 lead to a recessive syndrome in humans that includes periventricular neuronal heterotopia. Reducing the expression of Dchs1 or Fat4 within mouse embryonic neuroepithelium increased progenitor cell numbers and reduced their differentiation into neurons, resulting in the heterotopic accumulation of cells below the neuronal layers in the neocortex, reminiscent of the human phenotype. These effects were countered by concurrent knockdown of Yap, a transcriptional effector of the Hippo signaling pathway. These findings implicate Dchs1 and Fat4 upstream of Yap as key regulators of mammalian neurogenesis.

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Figure 1: Homozygous or compound heterozygous mutations in FAT4 or DCHS1 result in VMS.
Figure 2: FAT4 is expressed in the embryonic human cerebral cortex, and germline Fat4−/− mice do not exhibit neuronal heterotopia.
Figure 3: Abnormal distribution of neuroprogenitor cells with mouse embryonic cortices electroporated with shFat4 or shDchs1.
Figure 4: Knockdown of Fat4 or Dchs1 leads to increased proliferation of neuroprogenitor cells and accumulation of neuronal precursors.
Figure 5: Knockdown of Yap, a transcriptional activator negatively regulated by Hippo signaling, rescues the proliferation and differentiation phenotype produced by shRNA-mediated knockdown of Fat4 or Dchs1.

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Acknowledgements

We thank the families participating in this study for their involvement. This work was supported by funding from Cure Kids New Zealand and the Health Research Council of New Zealand (10/402) (S.P.R.), the Department of Health through the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre award to Guy's and St. Thomas' NHS Foundation Trust in partnership with King's College London and King's College Hospital NHS Foundation Trust (M.A.S.), Deutsche Forschungsgemeinschaft:SFB 817, Synergy and the Bundesministerium für Bildung und Forschung (M.G. and S.C.). The human embryonic and fetal material was provided by the joint Medical Research Council (grant G0700089)/Wellcome Trust (grant GR082557) Human Developmental Biology Resource. We thank F. Calzolari for the design of the Yap miRNA, P. Malatesta (Department of Experimental Medicine (DiMES), University of Genoa), K. Guan (Life Sciences Institute, University of Michigan) and S. Piccolo (Department of Molecular Medicine, University of Padua School of Medicine) for sharing plasmids and T. Öztürk and A. Waiser for excellent technical support.

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Authors and Affiliations

  1. Helmholtz Center Munich, German Research Center for Environmental Health, Institute for Stem Cell Research, Neuherberg, Germany

    Silvia Cappello, Simona Lange, Melanie Einsiedler & Magdalena Götz

  2. Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand

    Mary J Gray, Zandra A Jenkins, Tim Morgan, Nadia Preitner & Stephen P Robertson

  3. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada

    Caroline Badouel & Helen McNeill

  4. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada

    Caroline Badouel & Helen McNeill

  5. Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, Quebec, Canada

    Myriam Srour, Fadi F Hamdan & Jacques L Michaud

  6. Department of Obstetrics and Gynecology, Mount Sinai Hospital, Toronto, Ontario, Canada

    David Chitayat, Tami Uster & Jackie Thomas

  7. The Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, Toronto, Ontario, Canada

    David Chitayat & Tami Uster

  8. Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada

    David Chitayat

  9. Department of Laboratory Medicine and Pathobiology, Mount Sinai Hospital, Toronto, Ontario, Canada

    Patrick Shannon

  10. Human Development Biology Resource, Institute of Child Health, London, UK

    Victoria Morrison

  11. Institut für Klinische Genetik, Technische Universität Dresden, Dresden, Germany

    Nataliya Di Donato

  12. Centre de Génétique Humaine, Université de Franche-Comté, Besançon, France

    Lionel Van Maldergem

  13. Medizinisches Genetisches Zentrum, Munich, Germany

    Teresa Neuhann

  14. Department of Clinical Genetics, St. Michael's Hospital, Bristol, UK

    Ruth Newbury-Ecob

  15. Department of Medical Genetics, University Medical Center, Utrecht, The Netherlands

    Marielle Swinkells & Paulien Terhal

  16. North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children National Health Service (NHS) Trust, London, UK

    Louise C Wilson

  17. Department of Clinical Genetics, Vrije Universiteit Medical Center, Amsterdam, The Netherlands

    Petra J G Zwijnenburg

  18. Institute of Fundamental Sciences, Massey University, Palmerston North, New Zealand

    Andrew J Sutherland-Smith

  19. Department of Biochemistry, University of Otago, Dunedin, New Zealand

    Michael A Black

  20. Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand

    David Markie

  21. Division of Genetics and Molecular Medicine, King's College London School of Medicine, Guy's Hospital, London, UK

    Michael A Simpson

  22. South West Thames Regional Genetics Service, St. Georges, NHS Healthcare Trust, London, UK

    Sahar Mansour

  23. Department of Physiological Genomics, University of Munich, Munich, Germany

    Magdalena Götz

  24. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany

    Magdalena Götz

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  1. Silvia Cappello
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Contributions

S.C., M.J.G., S.M., M.G. and S.P.R. conceived and designed the study. S.C., M.J.G., C.B., S.L., M.E., M. Srour, F.F.H., Z.A.J., T.M., N.P., V.M. and M.A.S. performed the experiments and analyzed the data in conjunction with A.J.S.-S., M.A.B., D.M., J.L.M., H.M., M.G. and S.P.R. D.C., T.U., J.T., P.S., N.D.D., L.V.M., T.N., R.N.-E., M. Swinkells, P.T., L.C.W., P.J.G.Z. and S.M. provided reagents, clinical information and analysis of human subjects. S.C., M.J.G., M.G. and S.P.R. wrote the manuscript, which all authors refined and approved.

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Correspondence to Magdalena Götz or Stephen P Robertson.

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Cappello, S., Gray, M., Badouel, C. et al. Mutations in genes encoding the cadherin receptor-ligand pair DCHS1 and FAT4 disrupt cerebral cortical development. Nat Genet 45, 1300–1308 (2013). https://doi.org/10.1038/ng.2765

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