Clustered gamma-protocadherins regulate cortical interneuron programmed cell death

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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.

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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

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Walter R Mancia Leon

NeuroSurgery, University of California San Francisco, San Francisco, United States

Competing interests
No competing interests declared.
Julien Spatazza

NeuroSurgery, University of California San Francisco, San Francisco, United States

Competing interests
No competing interests declared.
Benjamin Rakela

Physiology, University of California San Francisco, San Francisco, United States

Competing interests
No competing interests declared.
Ankita Chatterjee

NeuroSurgery, University of California San Francisco, San Francisco, United States

Competing interests
No competing interests declared.
Viraj Pande

Neurosurgery, University of California San Francisco, San Francisco CA, United States

Competing interests
No competing interests declared.
Tom Maniatis

Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States

Competing interests
No competing interests declared.
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.

"This ORCID iD identifies the author of this article:" 0000-0003-3998-5073
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.
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..

"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.

Copyright

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.