, 2011). At the cellular level, expression of DISC1 is developmentally regulated within the nervous system (Miyoshi et al., 2003) and DISC1 in turn regulates multiple processes of both embryonic and adult neurogenesis (Christian et al., 2010). At the molecular level, a large number of potential DISC1 binding partners have been identified from a yeast two-hybrid screen (Chubb et al., 2008), many of which are also involved in neurodevelopmental processes implicated in the pathophysiology of psychiatric diseases. Regarded Vemurafenib mw as an “edge piece” of psychiatric genetics, DISC1 may thus provide an entry point to understand molecular mechanisms and etiology underlying

complex psychiatric disorders. Using a combinatorial approach to analyze the effect of genetic manipulations on individual neurons in the animal model, biochemical interactions of endogenous proteins in a homogenous cell population, and genetic associations

in clinical cohorts, we demonstrate two parallel pathways for FEZ1 and NDEL1 that independently cooperate with DISC1 to regulate different aspects of CX-5461 neuronal development and risk for schizophrenia. In the dentate gyrus of the hippocampus, a region implicated in schizophrenia pathophysiology (Harrison, 2004), neurogenesis continues throughout life in all mammals and contributes to specific brain functions (Zhao et al., 2008). Adult hippocampal neurogenesis provides a unique model system for dissecting signaling mechanisms that regulate neurodevelopment and

offers several distinct advantages for molecular analysis, including a prolonged developmental time course for more precise temporal resolution, a single neuronal subtype, Digestive enzyme and amenability to birth-dating, lineage tracing, and genetic manipulations (Christian et al., 2010). Using this in vivo model system, we have identified novel functions of FEZ1 in regulating dendritic growth and soma size of newborn dentate granule cells in the adult hippocampus (Figure 1). Furthermore, results from concomitant suppression of DISC1 and FEZ1 support a synergistic interaction between these two proteins in regulating dendritic growth in vivo (Figure 3). In parallel, the NDEL1-DISC1 interaction regulates a complementary subset of developmental processes, namely, neuronal positioning and development of primary dendrites (Duan et al., 2007). Interestingly, there is no apparent synergistic interaction between FEZ1 and NDEL1 in regulating neuronal development (Figure 4) and no protein-protein interaction in the absence of DISC1 (Figure 5). These results illustrate two discrete pathways associated with the DISC1 interactome that, in conjunction, account for most of the DISC1-mediated effects in orchestrating development of newborn neurons during adult hippocampal neurogenesis (Table 1).