1. Developmental Biology
  2. Neuroscience
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Clustered gamma-protocadherins regulate cortical interneuron programmed cell death

  1. Walter R Mancia Leon
  2. Julien Spatazza
  3. Benjamin Rakela
  4. Ankita Chatterjee
  5. Viraj Pande
  6. Tom Maniatis
  7. Andrea R Hasenstaub
  8. Michael P Stryker
  9. Arturo Alvarez-Buylla  Is a corresponding author
  1. University of California San Francisco, United States
  2. Columbia University, United States
  3. University of California, San Francisco, United States
Research Article
  • Cited 8
  • Views 1,396
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Cite this article as: eLife 2020;9:e55374 doi: 10.7554/eLife.55374

Abstract

Cortical function critically depends on inhibitory/excitatory balance. Cortical inhibitory interneurons (cINs) are born in the ventral forebrain and migrate into cortex, where their numbers are adjusted by programmed cell death. Here we show that loss of clustered gamma protocadherins (Pcdhg), but not of genes in the alpha or beta clusters, increased dramatically cIN BAX-dependent cell death in mice. Surprisingly, electrophysiological and morphological properties of Pcdhg-deficient and wild-type cINs during the period of cIN cell death were indistinguishable. Co-transplantation of wild-type with Pcdhg-deficient interneuron precursors further reduced mutant cIN survival, but the proportion of mutant and wild-type cells undergoing cell death was not affected by their density. Transplantation also allowed us to test for the contribution of Pcdhg isoforms to the regulation of cIN cell death. We conclude that Pcdhg, specifically Pcdhgc3, Pcdhgc4, and Pcdhgc5, play a critical role in regulating cIN survival during the endogenous period of programmed cIN death.

Data availability

Data generated for this study are included in the manuscript and source data files have been provided for Figures 1 to 13.

Article and author information

Author details

  1. Walter R Mancia Leon

    NeuroSurgery, University of California San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  2. Julien Spatazza

    NeuroSurgery, University of California San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  3. Benjamin Rakela

    Physiology, University of California San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  4. Ankita Chatterjee

    NeuroSurgery, University of California San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  5. Viraj Pande

    Neurosurgery, University of California San Francisco, San Francisco CA, United States
    Competing interests
    No competing interests declared.
  6. Tom Maniatis

    Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States
    Competing interests
    No competing interests declared.
  7. Andrea R Hasenstaub

    Center for Integrative Neuroscience and Coleman Memorial Laboratory, Department of Otolaryngology-Head and Neck Surgery, University of California San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3998-5073
  8. Michael P Stryker

    Center for Integrative Neuroscience, Department of Physiology, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  9. Arturo Alvarez-Buylla

    Center for Integrative Neuroscience and Coleman Memorial Laboratory, Department of Otolaryngology-Head and Neck Surgery, University of California San Francisco, San Francisco, United States
    For correspondence
    alvarezbuyllaa@ucsf.edu
    Competing interests
    Arturo Alvarez-Buylla, is cofounder, serves on the scientific advisory board, and owns shares in Neurona Therapeutics..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1920-6514

Funding

National Institutes of Health (R01NS028478)

  • Arturo Alvarez-Buylla

National Institutes of Health (EY02517)

  • Arturo Alvarez-Buylla

National Institutes of Health (R01DC014101)

  • Andrea R Hasenstaub

National Institutes of Health (R01EY025174)

  • Michael P Stryker

National Institutes of Health (5F32EY029935)

  • Benjamin Rakela
  • Michael P Stryker

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

Ethics

Animal experimentation: Data presented in this study were acquired following the University of California, San Francisco (UCSF) Institutional Animal Care Committee guidelines under the following protocols: AN178775-02C, AN180588, AN175872.

Reviewing Editor

  1. Sonia Garel, Ecole Normale Superieure, France

Publication history

  1. Received: January 22, 2020
  2. Accepted: July 6, 2020
  3. Accepted Manuscript published: July 7, 2020 (version 1)
  4. Version of Record published: July 21, 2020 (version 2)

Copyright

© 2020, Mancia Leon 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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