Cc2d1a, a C2 domain containing protein linked to nonsyndromic mental retardation, controls functional maturation of...

Cc2d1a is an evolutionarily conserved protein composed of NH(2)-terminal Drosophila melanogaster 14 domain (DM14) domains and a COOH-terminal C2 domain. Human patients with homozygotic mutation in the gene suffer from nonsyndromic mental retardation, implying that Cc2d1a functions in the central nervous system. To examine the physiological role of the Cc2d1a, we generated and analyzed Cc2d1a knockout (KO) mice. Cc2d1a KO mice die soon after birth, apparently because of their inability to breathe. Histological analysis of Cc2d1a KO animals did not identify any structural defects in the peripheral respiratory apparatus. However, functional analysis of synapses formed between Cc2d1a-deficient cortical neurons revealed a robust increase in the pace of maturation of evoked synaptic responses as well as synaptic vesicle trafficking. This synaptic anomaly was rescued by reintroducing full-length Cc2d1a but not C2-domain-deletion mutant, underscoring the functional importance of C2 domain. Our data suggest that Cc2d1a is required for mouse survival and performs essential function in controlling functional maturation of synapses.