The clustered gamma protocadherin PcdhγC4 isoform regulates cortical interneuron programmed cell death in the mouse cortex

Walter R Mancia Leon; David M Steffen; Fiona R Dale-Huang; Benjamin Rakela; Arnar Breevoort; Ricardo Romero-Rodriguez; Andrea R Hasenstaub; Michael P Stryker; Joshua A Weiner; Arturo Alvarez-Buylla

doi:10.1073/pnas.2313596120

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The clustered gamma protocadherin PcdhγC4 isoform regulates cortical interneuron programmed cell death in the mouse cortex

Journal article

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The clustered gamma protocadherin PcdhγC4 isoform regulates cortical interneuron programmed cell death in the mouse cortex

Walter R Mancia Leon, David M Steffen, Fiona R Dale-Huang, Benjamin Rakela, Arnar Breevoort, Ricardo Romero-Rodriguez, Andrea R Hasenstaub, Michael P Stryker, Joshua A Weiner and Arturo Alvarez-Buylla

Proceedings of the National Academy of Sciences - PNAS, Vol.121(6), e2313596120

02/06/2024

DOI: 10.1073/pnas.2313596120

PMCID: PMC10861877

PMID: 38285948

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Abstract

Cortical inhibitory interneurons (cINs) are born in the ventral forebrain and migrate into the cortex where they make connections with locally produced excitatory glutamatergic neurons. Cortical function critically depends on the number of cINs, which is also key to establishing the appropriate inhibitory/excitatory balance. The final number of cINs is determined during a postnatal period of programmed cell death (PCD) when ~40% of the young cINs are eliminated. Previous work shows that the loss of clustered gamma protocadherins (Pcdhgs), but not of genes in the or clusters, dramatically increased BAX-dependent cIN PCD. Here, we show that is highly expressed in cINs of the mouse cortex and that this expression increases during PCD. The sole deletion of the PcdhγC4 isoform, but not of the other 21 isoforms in the gene cluster, increased cIN PCD. Viral expression of the in cIN lacking the function of the entire cluster, rescued most of these cells from cell death. We conclude that plays a critical role in regulating the survival of cINs during their normal period of PCD. This highlights how a single isoform of the cluster, which has been linked to human neurodevelopmental disorders, is essential to adjust cIN cell numbers during cortical development.

Animals

Apoptosis - genetics

Cerebral Cortex - physiology

Humans

Interneurons - physiology

Mice

Neurons - metabolism

Protein Isoforms - genetics

Protein Isoforms - metabolism

Protocadherins

Details

Title: Subtitle: The clustered gamma protocadherin PcdhγC4 isoform regulates cortical interneuron programmed cell death in the mouse cortex
Creators: Walter R Mancia Leon - Broad Center
David M Steffen - University of Iowa
Fiona R Dale-Huang - Broad Center
Benjamin Rakela - University of California, San Francisco
Arnar Breevoort - University of California, San Francisco
Ricardo Romero-Rodriguez - Broad Center
Andrea R Hasenstaub - University of California, San Francisco
Michael P Stryker - University of California, San Francisco
Joshua A Weiner - University of Iowa
Arturo Alvarez-Buylla - Broad Center
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.121(6), e2313596120
DOI: 10.1073/pnas.2313596120
PMID: 38285948
PMCID: PMC10861877
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Grant note: R01MH122478 / NIH HHS EY02517 / NIH HHS R01EY002874 / NIH HHS NS055272 / NIH HHS R01NS116598 / NIH HHS NS028478 / NIH HHS NS090030 / NIH HHS R01EY031059 / NIH HHS
Language: English
Date published: 02/06/2024
Academic Unit: Liberal Arts and Science Admin; Psychiatry; Iowa Neuroscience Institute; Biology
Record Identifier: 9984554854302771

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