Journal article
A unique role for Protocadherin γC3 in promoting dendrite arborization through an Axin1-dependent mechanism
The Journal of neuroscience, Vol.43(6), pp.918-935
01/05/2023
DOI: 10.1523/JNEUROSCI.0729-22.2022
PMCID: PMC9908324
PMID: 36604170
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.
Details
- Title: Subtitle
- A unique role for Protocadherin γC3 in promoting dendrite arborization through an Axin1-dependent mechanism
- Creators
- David M Steffen - University of IowaCamille M Hanes - Department of Biology, The University of Iowa, Iowa City, IA 52242Kar Men Mah - Department of Biology, The University of Iowa, Iowa City, IA 52242Paula Valiño Ramos - Department of Biology, The University of Iowa, Iowa City, IA 52242Peter J Bosch - University of IowaDalton C Hinz - Department of Psychological and Brain Sciences, Program in Neuroscience, Iowa Neuroscience Institute, University of Iowa, Iowa City, IA 52242Jason J Radley - University of IowaRobert W Burgess - Jackson LaboratoryAndrew M Garrett - Wayne State UniversityJoshua A Weiner - Department of Biology, The University of Iowa, Iowa City, IA 52242
- Resource Type
- Journal article
- Publication Details
- The Journal of neuroscience, Vol.43(6), pp.918-935
- DOI
- 10.1523/JNEUROSCI.0729-22.2022
- PMID
- 36604170
- PMCID
- PMC9908324
- ISSN
- 0270-6474
- eISSN
- 1529-2401
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health, award: R01 NS055272, R21 NS090030
- Language
- English
- Date published
- 01/05/2023
- Academic Unit
- Neurology; Liberal Arts and Science Admin; Psychiatry; Psychological and Brain Sciences; Iowa Neuroscience Institute; Biology
- Record Identifier
- 9984355860302771
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