, 2001 and Millar et al., 2000). Additional
linkage studies with DISC1 mutations further support its role in influencing risk for psychosis and autistic spectrum disorders ( Chubb et al., 2008). Functional studies in animal models suggest that DISC1 plays a multifaceted role in both embryonic and postnatal neurogenesis in vivo. Exogenous manipulation of DISC1 results in a spectrum of neuronal abnormalities, depending on the timing and anatomical locus of perturbation. During embryonic cortical development, knockdown of DISC1 in E13 embryos accelerates cell cycle exit and neuronal differentiation ( Mao et al., 2009), whereas knockdown at E14.5 leads to inhibition of neuronal BTK inhibitor screening library migration and disorganized dendritic arbors ( Kamiya et al., 2005). During adult CP-690550 purchase hippocampal
neurogenesis, suppression of DISC1 also leads to decreased proliferation of neural progenitors ( Mao et al., 2009) and an array of neurodevelopmental defects in newborn dentate granule cells, including soma hypertrophy, mispositioning, impaired axonal targeting, and accelerated dendritic growth and synaptogenesis ( Duan et al., 2007, Faulkner et al., 2008 and Kim et al., 2009). The signaling mechanisms by which DISC1 regulates neurogenesis in vivo have just begun to be explored. For example, DISC1 regulates proliferation of neural progenitors through interaction with GSK3β (Mao et al., 2009), whereas it regulates development of newborn dentate granule cells through direct interaction with KIAA1212/Girdin in the hippocampus (Enomoto et al., 2009 and Kim et al., 2009). NDEL1 (nuclear distribution gene E-like homolog 1) also directly interacts
with DISC1 (Morris et al., 2003 and Ozeki et al., 2003). Knockdown of NDEL1 in newborn neurons in the adult hippocampus leads to primary DNA ligase defects in neuronal positioning and appearance of ectopic dendrites, representing some, but not all, of phenotypes observed with DISC1 suppression (Duan et al., 2007). This result suggests the existence of additional mechanisms by which DISC1 regulates other aspects of neuronal development. Indeed, early biochemical and yeast two-hybrid screens have identified a large number of DISC1 binding partners, many of which are known to be involved in neurodevelopmental processes (Camargo et al., 2007). While these studies established DISC1 as a scaffold protein, the functional role of the majority of these potential interactions in neuronal development remains to be demonstrated in vivo. Understanding mechanisms by which DISC1 differentially regulates distinct neurodevelopmental processes through its binding partners may reveal how dysfunction of DISC1 contributes to a wide spectrum of psychiatric and mental disorders.