Molumby_2017_Cell.Rep_18_2702

The 22 gamma-Protocadherin (gamma-Pcdh) cell adhesion molecules are critical for the elaboration of complex dendritic arbors in the cerebral cortex. Here, we provide evidence that the gamma-Pcdhs negatively regulate synapse development by inhibiting the postsynaptic cell adhesion molecule, neuroligin-1 (Nlg1). Mice lacking all gamma-Pcdhs in the forebrain exhibit significantly increased dendritic spine density in vivo, while spine density is significantly decreased in mice overexpressing one of the 22 gamma-Pcdh isoforms. Co-expression of gamma-Pcdhs inhibits the ability of Nlg1 to increase spine density and to induce presynaptic differentiation in hippocampal neurons in vitro. The gamma-Pcdhs physically interact in cis with Nlg1 both in vitro and in vivo, and we present evidence that this disrupts Nlg1 binding to its presynaptic partner neurexin1beta. Together with prior work, these data identify a mechanism through which gamma-Pcdhs could coordinate dendrite arbor growth and complexity with spine maturation in the developing brain.