A transient role of the ciliary gene Inpp5e in controlling direct versus indirect neurogenesis in cortical development

  1. Kerstin Hasenpusch-Theil
  2. Christine Laclef
  3. Matt Colligan
  4. Eamon Fitzgerald
  5. Katherine Howe
  6. Emily Carroll
  7. Shaun R Abrams
  8. Jeremy F Reiter
  9. Sylvie Schneider-Maunoury
  10. Thomas Theil  Is a corresponding author
  1. University of Edinburgh, United Kingdom
  2. Sorbonne University, France
  3. University of California, San Francisco, United States
  4. Sorbonne Universite Paris, France

Abstract

During the development of the cerebral cortex, neurons are generated directly from radial glial cells or indirectly via basal progenitors. The balance between these division modes determines the number and types of neurons formed in the cortex thereby affecting cortical functioning. Here, we investigate the role of primary cilia in controlling the decision between forming neurons directly or indirectly. We show that a mutation in the ciliary gene Inpp5e leads to a transient increase in direct neurogenesis and subsequently to an overproduction of layer V neurons in newborn mice. Loss of Inpp5e also affects ciliary structure coinciding with reduced Gli3 repressor levels. Genetically restoring Gli3 repressor rescues the decreased indirect neurogenesis in Inpp5e mutants. Overall, our analyses reveal how primary cilia determine neuronal subtype composition of the cortex by controlling direct versus indirect neurogenesis. These findings have implications for understanding cortical malformations in ciliopathies with INPP5E mutations.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Kerstin Hasenpusch-Theil

    Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Christine Laclef

    Institut de Biologie Paris Seine, Sorbonne University, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Matt Colligan

    Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6553-8915
  4. Eamon Fitzgerald

    Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Katherine Howe

    Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Emily Carroll

    Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Shaun R Abrams

    Deprartment of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Jeremy F Reiter

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Sylvie Schneider-Maunoury

    Institut de Biologie Paris Seine, Sorbonne Universite Paris, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  10. Thomas Theil

    Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
    For correspondence
    thomas.theil@ed.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6590-8309

Funding

Biotechnology and Biological Sciences Research Council (BB/P00122X/1)

  • Thomas Theil

NIH Clinical Center (R01GM095941)

  • Jeremy F Reiter

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experimental work was carried out in accordance with the UK Animals (Scientific Procedures) Act 1986 and UK Home Office guidelines under the project license numer P53864D41. All protocols were reviewed and approved by the named veterinary surgeons of the College of Medicine and Veterinary Medicine, the University of Edinburgh, prior to the commencement of experimental work.

Reviewing Editor

  1. Fadel Tissir, Universite' Catholique de Louvain, Belgium

Publication history

  1. Received: April 22, 2020
  2. Accepted: August 24, 2020
  3. Accepted Manuscript published: August 25, 2020 (version 1)
  4. Version of Record published: September 9, 2020 (version 2)

Copyright

© 2020, Hasenpusch-Theil et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Kerstin Hasenpusch-Theil
  2. Christine Laclef
  3. Matt Colligan
  4. Eamon Fitzgerald
  5. Katherine Howe
  6. Emily Carroll
  7. Shaun R Abrams
  8. Jeremy F Reiter
  9. Sylvie Schneider-Maunoury
  10. Thomas Theil
(2020)
A transient role of the ciliary gene Inpp5e in controlling direct versus indirect neurogenesis in cortical development
eLife 9:e58162.
https://doi.org/10.7554/eLife.58162

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