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A unique role for Protocadherin γC3 in promoting dendrite arborization through an Axin1-dependent mechanism
Journal article   Open access   Peer reviewed

A unique role for Protocadherin γC3 in promoting dendrite arborization through an Axin1-dependent mechanism

David M Steffen, Camille M Hanes, Kar Men Mah, Paula Valiño Ramos, Peter J Bosch, Dalton C Hinz, Jason J Radley, Robert W Burgess, Andrew M Garrett and Joshua A Weiner
The Journal of neuroscience, Vol.43(6), pp.918-935
01/05/2023
DOI: 10.1523/JNEUROSCI.0729-22.2022
PMCID: PMC9908324
PMID: 36604170
url
https://doi.org/10.1523/JNEUROSCI.0729-22.2022View
Published (Version of record) Open Access

Abstract

The establishment of a functional cerebral cortex depends on the proper execution of multiple developmental steps, culminating in dendritic and axonal outgrowth and the formation and maturation of synaptic connections. Dysregulation of these processes can result in improper neuronal connectivity, including that associated with various neurodevelopmental disorders. The γ-Protocadherins (γ-Pcdhs), a family of 22 distinct cell adhesion molecules (CAMs) that share a C-terminal cytoplasmic domain, are involved in multiple aspects of neurodevelopment including neuronal survival, dendrite arborization, and synapse development. The extent to which individual γ-Pcdh family members play unique common roles remains unclear. We demonstrated previously that the γ-Pcdh-C3 isoform (γC3), its unique "variable" cytoplasmic domain (VCD), interacts in cultured cells with Axin1, a Wnt-pathway scaffold protein that regulates the differentiation and morphology of neurons. Here, we confirm that γC3 and Axin1 interact in the cortex and show that both male and female mice specifically lacking γC3 exhibit disrupted Axin1 localization to synaptic fractions, without obvious changes in dendritic spine density or morphology. However, both male and female γC3 knockout mice exhibit severely decreased dendritic complexity of cortical pyramidal neurons that is not observed in mouse lines lacking several other γ-Pcdh isoforms. Combining knockout with rescue constructs in cultured cortical neurons pooled from both male and female mice, we show that γC3 promotes dendritic arborization through an Axin1-dependent mechanism mediated through its VCD. Together, these data identify a novel mechanism though which γC3 uniquely regulates the formation of cortical circuitry. The complexity of a neuron's dendritic arbor is critical for its function. We showed previously that the γ-Protocadherin (γ-Pcdh) family of 22 cell adhesion molecules promotes arborization during development; it remained unclear whether individual family members played unique roles. Here, we show that one γ-Pcdh isoform, γC3, interacts in the brain with Axin1, a scaffolding protein known to influence dendrite development. A CRISPR/Cas9-generated mutant mouse line lacking γC3 (but not lines lacking other γ-Pcdhs) exhibits severely reduced dendritic complexity of cerebral cortex neurons. Using cultured γC3 knockout neurons and a variety of rescue constructs, we confirm that the γC3 cytoplasmic domain promotes arborization through an Axin1-dependent mechanism. Thus, γ-Pcdh isoforms are not interchangeable, but rather can play unique neurodevelopmental roles.

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