A Unique Role for Protocadherin yC3 in Promoting Dendrite Arborization through an Axin1-Dependent Mechanism

The establishment of a functional cerebral cortex depends on the proper execution of multiple developmental steps, culminat-ing 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 y-Protocadherins (y-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 devel-opment. The extent to which individual y-Pcdh family members play unique versus common roles remains unclear. We dem-onstrated previously that the y-Pcdh-C3 isoform (yC3), via 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 yC3 and Axin1 interact in the cortex in vivo and show that both male and female mice specifically lacking yC3 exhibit disrupted Axin1 localization to synaptic fractions, without obvious changes in dendritic spine density or morphology. However, both male and female yC3 knock-out mice exhibit severely decreased dendritic complexity of cortical pyramidal neurons that is not observed in mouse lines lacking several other y-Pcdh isoforms. Combining knock-out with res-cue constructs in cultured cortical neurons pooled from both male and female mice, we show that yC3 promotes dendritic arborization through an Axin1-dependent mechanism mediated through its VCD. Together, these data identify a novel mech-anism through which yC3 uniquely regulates the formation of cortical circuitry.

Automated summary

The establishment of a functional cerebral cortex relies on the proper execution of various developmental steps, which includes dendritic and axonal outgrowth, synaptic connection formation and maturation. Dysregulation of these processes can result in improper neuronal connectivity, including neurodevelopmental disorders. The y-Protocadherins (y-Pcdhs) are involved in multiple aspects of neurodevelopment, including neuronal survival, dendrite arborization, and synapse development. The specific role of each individual y-Pcdh family member remains unclear.