A Unique Role for Protocadherin γC3 in Promoting Dendrite Arborization through an Axin1-Dependent Mechanism

Area of Science:

• Neuroscience
• Developmental Biology
• Molecular Biology

Background:

• The cerebral cortex requires precise development, including neuronal outgrowth and synapse formation, for function.
• Dysregulation of neurodevelopment can lead to neurodevelopmental disorders.
• The γ-Protocadherin (γ-Pcdh) family, including γC3, are cell adhesion molecules involved in neuronal development, but individual roles are unclear.

Purpose of the Study:

• To investigate the unique role of the γ-Protocadherin-C3 (γC3) isoform in cerebral cortex development.
• To determine the interaction between γC3 and Axin1 in vivo and its role in neuronal morphology.
• To elucidate the mechanism by which γC3 influences dendritic arborization.

Main Methods:

• Generated γC3 knock-out mice using CRISPR/Cas9.
• Confirmed γC3 and Axin1 interaction in vivo in the cortex.
• Analyzed dendritic complexity and spine density in γC3 deficient mice.
• Utilized cultured cortical neurons with rescue constructs to study γC3 function.

Main Results:

• γC3 deficiency in mice disrupted Axin1 localization to synaptic fractions.
• γC3 knock-out mice showed severely decreased dendritic complexity of cortical pyramidal neurons.
• This reduction in dendritic complexity was not observed in mice lacking other γ-Pcdh isoforms.
• γC3 promotes dendritic arborization via an Axin1-dependent mechanism mediated by its unique cytoplasmic domain.

Conclusions:

• γC3 plays a unique and critical role in regulating dendritic arborization of cortical neurons.
• The interaction between γC3 and Axin1 is essential for establishing proper neuronal connectivity.
• γ-Protocadherin isoforms are not functionally redundant and have distinct developmental roles.