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

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.

Reviewing Editor

  1. Sonia Garel, Ecole Normale Superieure, France

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.

Version 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.

Metrics

  • 2,804
    Page views
  • 396
    Downloads
  • 25
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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
(2020)
Clustered gamma-protocadherins regulate cortical interneuron programmed cell death
eLife 9:e55374.
https://doi.org/10.7554/eLife.55374

Share this article

https://doi.org/10.7554/eLife.55374

Further reading

    1. Developmental Biology
    2. Neuroscience
    Tariq Zaman, Daniel Vogt ... Michael R Williams
    Research Article

    The cell-type-specific expression of ligand/receptor and cell-adhesion molecules is a fundamental mechanism through which neurons regulate connectivity. Here, we determine a functional relevance of the long-established mutually exclusive expression of the receptor tyrosine kinase Kit and the trans-membrane protein Kit Ligand by discrete populations of neurons in the mammalian brain. Kit is enriched in molecular layer interneurons (MLIs) of the cerebellar cortex (i.e., stellate and basket cells), while cerebellar Kit Ligand is selectively expressed by a target of their inhibition, Purkinje cells (PCs). By in vivo genetic manipulation spanning embryonic development through adulthood, we demonstrate that PC Kit Ligand and MLI Kit are required for, and capable of driving changes in, the inhibition of PCs. Collectively, these works in mice demonstrate that the Kit Ligand/Kit receptor dyad sustains mammalian central synapse function and suggest a rationale for the affiliation of Kit mutation with neurodevelopmental disorders.

    1. Developmental Biology
    2. Neuroscience
    Smrithi Prem, Bharati Dev ... Emanuel DiCicco-Bloom
    Research Article

    Autism spectrum disorder (ASD) is defined by common behavioral characteristics, raising the possibility of shared pathogenic mechanisms. Yet, vast clinical and etiological heterogeneity suggests personalized phenotypes. Surprisingly, our iPSC studies find that six individuals from two distinct ASD-subtypes, idiopathic and 16p11.2 deletion, have common reductions in neural precursor cell (NPC) neurite outgrowth and migration even though whole genome sequencing demonstrates no genetic overlap between the datasets. To identify signaling differences that may contribute to these developmental defects, an unbiased phospho-(p)-proteome screen was performed. Surprisingly despite the genetic heterogeneity, hundreds of shared p-peptides were identified between autism subtypes including the mTOR pathway. mTOR signaling alterations were confirmed in all NPCs across both ASD-subtypes, and mTOR modulation rescued ASD phenotypes and reproduced autism NPC associated phenotypes in control NPCs. Thus, our studies demonstrate that genetically distinct ASD subtypes have common defects in neurite outgrowth and migration which are driven by the shared pathogenic mechanism of mTOR signaling dysregulation.