γ-Protocadherins Control Cortical Dendrite Arborization by Regulating the Activity of a FAK/PKC/MARCKS Signaling Pathway

The 22 gamma-protocadherins (gamma-Pcdhs) potentially specify thousands of distinct homophilic adhesive interactions in the brain. Neonatal lethality of mice lacking the Pcdh-gamma gene cluster has, however, precluded analysis of many brain regions. Here, we use a conditional Pcdh-gamma allele to restrict mutation to the cerebral cortex and find that, in contrast to other central nervous system phenotypes, loss of gamma-Pcdhs in cortical neurons does not affect their survival or result in reduced synaptic density. Instead, mutant cortical neurons exhibit severely reduced dendritic arborization. Mutant cortices have aberrantly high levels of protein kinase C (PKC) activity and of phosphorylated (inactive) myristoylated alanine-rich C-kinase substrate, a PKC target that promotes arborization. Dendrite complexity can be rescued in Pcdh-gamma mutant neurons by inhibiting PKC, its upstream activator phospholipase C, or the gamma-Pcdh binding partner focal adhesion kinase. Our results reveal a distinct role for the gamma-Pcdhs in cortical development and identify a signaling pathway through which they play this role.