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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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.

Author information

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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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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Magdalena Götz or Stephen P Robertson.

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https://doi.org/10.1038/ng.2765

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