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Neurosci."],"published-print":{"date-parts":[[2023,2,8]]},"abstract":"<jats:p>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 \u03b3-Protocadherins (\u03b3-Pcdhs), a family of 22 distinct cell adhesion molecules 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 \u03b3-Pcdh family members play unique versus common roles remains unclear. We demonstrated previously that the \u03b3-Pcdh-C3 isoform (\u03b3C3), via its unique \u201cvariable\u201d 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 \u03b3C3 and Axin1 interact in the cortex<jats:italic>in vivo<\/jats:italic>and show that both male and female mice specifically lacking \u03b3C3 exhibit disrupted Axin1 localization to synaptic fractions, without obvious changes in dendritic spine density or morphology. However, both male and female \u03b3C3 knock-out mice exhibit severely decreased dendritic complexity of cortical pyramidal neurons that is not observed in mouse lines lacking several other \u03b3-Pcdh isoforms. Combining knock-out with rescue constructs in cultured cortical neurons pooled from both male and female mice, we show that \u03b3C3 promotes dendritic arborization through an Axin1-dependent mechanism mediated through its VCD. Together, these data identify a novel mechanism through which \u03b3C3 uniquely regulates the formation of cortical circuitry.<\/jats:p><jats:p><jats:bold>SIGNIFICANCE STATEMENT<\/jats:bold>The complexity of a neuron's dendritic arbor is critical for its function. We showed previously that the \u03b3-Protocadherin (\u03b3-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 \u03b3-Pcdh isoform, \u03b3C3, interacts in the brain with Axin1, a scaffolding protein known to influence dendrite development. A CRISPR\/Cas9-generated mutant mouse line lacking \u03b3C3 (but not lines lacking other \u03b3-Pcdhs) exhibits severely reduced dendritic complexity of cerebral cortex neurons. Using cultured \u03b3C3 knock-out neurons and a variety of rescue constructs, we confirm that the \u03b3C3 cytoplasmic domain promotes arborization through an Axin1-dependent mechanism. Thus, \u03b3-Pcdh isoforms are not interchangeable, but rather can play unique neurodevelopmental roles.<\/jats:p>","DOI":"10.1523\/jneurosci.0729-22.2022","type":"journal-article","created":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T18:50:34Z","timestamp":1672944634000},"page":"918-935","source":"Crossref","is-referenced-by-count":23,"title":["A Unique Role for Protocadherin \u03b3C3 in Promoting Dendrite Arborization through an Axin1-Dependent Mechanism"],"prefix":"10.1523","volume":"43","author":[{"given":"David M.","family":"Steffen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Camille M.","family":"Hanes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kar Men","family":"Mah","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paula","family":"Vali\u00f1o 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