γ-Protocadherins regulate neuronal survival but are dispensable for circuit formation in retina

Abstract

Twenty-two tandemly arranged protocadherin-γ (Pcdh-γ) genes encode transmembrane proteins with distinct cadherin-related extracellular domains and a common intracellular domain. Genetic studies have implicated Pcdh-γ genes in the regulation of neuronal survival and synapse formation. Because mice lacking the Pcdh-γ cluster die perinatally, we generated conditional mutants to analyze roles of Pcdh-γ genes in the development and function of neural circuits. Retina-specific deletion of Pcdh-γs led to accentuation of naturally occurring death of interneurons and retinal ganglion cells (RGCs) during the first two postnatal weeks. Nonetheless, many neuronal subtypes formed lamina-specific arbors. Blocking apoptosis by deletion of the pro-apoptotic gene Bax showed that even neurons destined to die formed qualitatively and quantitatively appropriate connections. Moreover, electrophysiological analysis indicated that processing of visual information was largely normal in the absence of Pcdh-γ genes. These results suggest that Pcdh-γ genes are dispensable for elaboration of specific connections in retina, but play a primary role in sculpting neuronal populations to appropriate sizes or proportions during the period of naturally occurring cell death.