, 2003). FEZ1 is a mammalian ortholog of the Caenorhabditis elegans UNC-76 protein, thought to be involved in nerve growth and fasciculation ( Bloom and Horvitz, 1997 and Kuroda et al., 1999). FEZ1 expression is developmentally regulated and appears to be abundant in the adult mouse dentate gyrus ( Miyoshi et al., 2003 and Sakae et al., 2008). In vitro, FEZ1 colocalizes with DISC1 at neuronal growth cones and regulates neurite outgrowth of PC12 cells ( Miyoshi et al., 2003). The role of FEZ1 in mammalian neuronal development in vivo is not well understood. Fez1 null mice exhibit hyperactivity and enhanced responsiveness to psychostimulants ( Sakae LY294002 et al.,

2008), supporting a potential contribution of FEZ1 dysfunction to schizophrenia. Single nucleotide polymorphism (SNP) and haplotype association analyses of the FEZ1 locus with schizophrenia have demonstrated a positive association in one cohort of

patients ( Yamada et al., 2004), but not in others ( Hodgkinson et al., 2007, Koga et al., 2007, Nicodemus et al., 2010 and Rastogi et al., 2009). Interestingly, there is a significant reduction of FEZ1 mRNA in both hippocampus and dorsolateral prefrontal cortex of schizophrenia patients and an association of the DISC1 genotype and FEZ1 mRNA levels ( Lipska et al., 2006). These findings raise the possibility that FEZ1 and DISC1 may cooperate to regulate both neuronal development and risk for schizophrenia. In the present selleck study, we used adult mouse else hippocampal neurogenesis as an in vivo cellular model to dissect signaling mechanisms by which DISC1 regulates different aspects of neuronal development. We showed that interaction between FEZ1 and DISC1 regulates dendritic development of newborn dentate granule cells in the adult brain. This functional association complements the parallel DISC1-NDEL1 interaction, which regulates positioning and morphogenesis of newborn neurons. Biochemically, endogenous DISC1 interacts with both

FEZ1 and NDEL1, whereas FEZ1 and NDEL1 do not appear to interact without DISC1. Furthermore, genetic association analyses in two clinical cohorts reveal an epistatic interaction between FEZ1 and DISC1, but not between FEZ1 and NDEL1, for an increased risk for schizophrenia. Together, our findings support a model in which DISC1 interacts with different partners to regulate distinct aspects of neuronal development and epistatic interactions between DISC1 and these genes may exacerbate neurodevelopmental deficits and confer an increased risk for schizophrenia. To explore signaling pathways underlying DISC1-dependent regulation of neuronal development, we generated retroviral vectors coexpressing GFP and specific short-hairpin RNAs (shRNAs) against mouse fez1 (see Experimental Procedures).