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• W2095751946 abstract "Disrupted-in Schizophrenia 1 (DISC1), a susceptibility gene for major mental disorders, encodes a scaffold protein that has a multifaceted impact on neuronal development. How DISC1 regulates different aspects of neuronal development is not well understood. Here, we show that Fasciculation and Elongation Protein Zeta-1 (FEZ1) interacts with DISC1 to synergistically regulate dendritic growth of newborn neurons in the adult mouse hippocampus, and that this pathway complements a parallel DISC1-NDEL1 interaction that regulates cell positioning and morphogenesis of newborn neurons. Furthermore, genetic association analysis of two independent cohorts of schizophrenia patients and healthy controls reveals an epistatic interaction between FEZ1 and DISC1, but not between FEZ1 and NDEL1, for risk of schizophrenia. Our findings support a model in which DISC1 regulates distinct aspects of neuronal development through its interaction with different intracellular partners and such epistasis may contribute to increased risk for schizophrenia. Disrupted-in Schizophrenia 1 (DISC1), a susceptibility gene for major mental disorders, encodes a scaffold protein that has a multifaceted impact on neuronal development. How DISC1 regulates different aspects of neuronal development is not well understood. Here, we show that Fasciculation and Elongation Protein Zeta-1 (FEZ1) interacts with DISC1 to synergistically regulate dendritic growth of newborn neurons in the adult mouse hippocampus, and that this pathway complements a parallel DISC1-NDEL1 interaction that regulates cell positioning and morphogenesis of newborn neurons. Furthermore, genetic association analysis of two independent cohorts of schizophrenia patients and healthy controls reveals an epistatic interaction between FEZ1 and DISC1, but not between FEZ1 and NDEL1, for risk of schizophrenia. Our findings support a model in which DISC1 regulates distinct aspects of neuronal development through its interaction with different intracellular partners and such epistasis may contribute to increased risk for schizophrenia. FEZ1 regulates dendritic growth and soma size during adult hippocampal neurogenesis FEZ1 interacts with DISC1 in regulating dendritic growth of newborn neurons FEZ1 and NDEL1 differentially mediate DISC1-dependent neuronal development Epistasis between FEZ1 and DISC1 influences the risk for schizophrenia An abiding principle of brain organization holds that the precise synaptic connectivity of neuronal networks determines brain functions. Conversely, pathological disturbances of this neuronal and synaptic patterning may contribute to the symptomatology of many neurological and psychiatric illnesses. Therefore, understanding molecular mechanisms that regulate neuronal development and connectivity can generate insight into the processes that govern the functional integrity of the developing and adult brain. In the hippocampus of the adult mammalian brain, new neurons are continually generated from neural stem cells throughout the lifespan of the organism (Lledo et al., 2006Lledo P.M. Alonso M. Grubb M.S. Adult neurogenesis and functional plasticity in neuronal circuits.Nat. Rev. Neurosci. 2006; 7: 179-193Crossref PubMed Scopus (1128) Google Scholar, Ming and Song, 2005Ming G.L. Song H. Adult neurogenesis in the mammalian central nervous system.Annu. Rev. Neurosci. 2005; 28: 223-250Crossref PubMed Scopus (1505) Google Scholar, Zhao et al., 2008Zhao C. Deng W. Gage F.H. Mechanisms and functional implications of adult neurogenesis.Cell. 2008; 132: 645-660Abstract Full Text Full Text PDF PubMed Scopus (2433) Google Scholar). Adult neurogenesis recapitulates the complete process of embryonic neuronal development, including proliferation and fate specification of neural progenitors, morphogenesis, axon and dendritic growth, migration, and synapse formation of neuronal progeny (Duan et al., 2008Duan X. Kang E. Liu C.Y. Ming G.L. Song H. Development of neural stem cell in the adult brain.Curr. Opin. Neurobiol. 2008; 18: 108-115Crossref PubMed Scopus (256) Google Scholar, Ming and Song, 2011Ming G.L. Song H. Adult neurogenesis in the mammalian brain: significant answers and significant questions.Neuron. 2011; 70: 687-702Abstract Full Text Full Text PDF PubMed Scopus (1818) Google Scholar). Many signaling pathways play conserved roles during embryonic and adult neurogenesis and disruption of many of these same pathways have also been implicated in the etiology of psychiatric disorders (Harrison and Weinberger, 2005Harrison P.J. Weinberger D.R. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence.Mol. Psychiatry. 2005; 10: 40-68, 5Crossref PubMed Scopus (1694) Google Scholar, Kempermann et al., 2008Kempermann G. Krebs J. Fabel K. The contribution of failing adult hippocampal neurogenesis to psychiatric disorders.Curr. Opin. Psychiatry. 2008; 21: 290-295Crossref PubMed Scopus (200) Google Scholar). There is a growing body of evidence demonstrating a convergent effect of genetic mutations that both confer susceptibility to psychiatric diseases and result in dysregulation of neuronal development, supporting a neurodevelopmental origin of these diseases. One prominent example of this genetic convergence is disrupted in schizophrenia-1 (DISC1), a gene initially identified at the breakpoint of a balanced (1;11) (q42;q14) chromosome translocation in a large Scottish family that segregates with schizophrenia and other major mental disorders (Blackwood et al., 2001Blackwood D.H. Fordyce A. Walker M.T. St Clair D.M. Porteous D.J. Muir W.J. Schizophrenia and affective disorders—cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family.Am. J. Hum. Genet. 2001; 69: 428-433Abstract Full Text Full Text PDF PubMed Scopus (631) Google Scholar, Millar et al., 2000Millar J.K. Wilson-Annan J.C. Anderson S. Christie S. Taylor M.S. Semple C.A. Devon R.S. St Clair D.M. Muir W.J. Blackwood D.H. Porteous D.J. Disruption of two novel genes by a translocation co-segregating with schizophrenia.Hum. Mol. Genet. 2000; 9: 1415-1423Crossref PubMed Scopus (1073) Google Scholar). Additional linkage studies with DISC1 mutations further support its role in influencing risk for psychosis and autistic spectrum disorders (Chubb et al., 2008Chubb J.E. Bradshaw N.J. Soares D.C. Porteous D.J. Millar J.K. The DISC locus in psychiatric illness.Mol. Psychiatry. 2008; 13: 36-64Crossref PubMed Scopus (474) Google Scholar). 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., 2009Mao Y. Ge X. Frank C.L. Madison J.M. Koehler A.N. Doud M.K. Tassa C. Berry E.M. Soda T. Singh K.K. et al.Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling.Cell. 2009; 136: 1017-1031Abstract Full Text Full Text PDF PubMed Scopus (638) Google Scholar), whereas knockdown at E14.5 leads to inhibition of neuronal migration and disorganized dendritic arbors (Kamiya et al., 2005Kamiya A. Kubo K. Tomoda T. Takaki M. Youn R. Ozeki Y. Sawamura N. Park U. Kudo C. Okawa M. et al.A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development.Nat. Cell Biol. 2005; 7: 1167-1178Crossref PubMed Scopus (445) Google Scholar). During adult hippocampal neurogenesis, suppression of DISC1 also leads to decreased proliferation of neural progenitors (Mao et al., 2009Mao Y. Ge X. Frank C.L. Madison J.M. Koehler A.N. Doud M.K. Tassa C. Berry E.M. Soda T. Singh K.K. et al.Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling.Cell. 2009; 136: 1017-1031Abstract Full Text Full Text PDF PubMed Scopus (638) Google Scholar) 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., 2007Duan X. Chang J.H. Ge S. Faulkner R.L. Kim J.Y. Kitabatake Y. Liu X.B. Yang C.H. Jordan J.D. Ma D.K. et al.Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain.Cell. 2007; 130: 1146-1158Abstract Full Text Full Text PDF PubMed Scopus (520) Google Scholar, Faulkner et al., 2008Faulkner R.L. Jang M.H. Liu X.B. Duan X. Sailor K.A. Kim J.Y. Ge S. Jones E.G. Ming G.L. Song H. Cheng H.J. Development of hippocampal mossy fiber synaptic outputs by new neurons in the adult brain.Proc. Natl. Acad. Sci. USA. 2008; 105: 14157-14162Crossref PubMed Scopus (171) Google Scholar, Kim et al., 2009Kim J.Y. Duan X. Liu C.Y. Jang M.H. Guo J.U. Pow-anpongkul N. Kang E. Song H. Ming G.L. DISC1 regulates new neuron development in the adult brain via modulation of AKT-mTOR signaling through KIAA1212.Neuron. 2009; 63: 761-773Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar). 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., 2009Mao Y. Ge X. Frank C.L. Madison J.M. Koehler A.N. Doud M.K. Tassa C. Berry E.M. Soda T. Singh K.K. et al.Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling.Cell. 2009; 136: 1017-1031Abstract Full Text Full Text PDF PubMed Scopus (638) Google Scholar), whereas it regulates development of newborn dentate granule cells through direct interaction with KIAA1212/Girdin in the hippocampus (Enomoto et al., 2009Enomoto A. Asai N. Namba T. Wang Y. Kato T. Tanaka M. Tatsumi H. Taya S. Tsuboi D. Kuroda K. et al.Roles of disrupted-in-schizophrenia 1-interacting protein girdin in postnatal development of the dentate gyrus.Neuron. 2009; 63: 774-787Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar, Kim et al., 2009Kim J.Y. Duan X. Liu C.Y. Jang M.H. Guo J.U. Pow-anpongkul N. Kang E. Song H. Ming G.L. DISC1 regulates new neuron development in the adult brain via modulation of AKT-mTOR signaling through KIAA1212.Neuron. 2009; 63: 761-773Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar). NDEL1 (nuclear distribution gene E-like homolog 1) also directly interacts with DISC1 (Morris et al., 2003Morris J.A. Kandpal G. Ma L. Austin C.P. DISC1 (Disrupted-In-Schizophrenia 1) is a centrosome-associated protein that interacts with MAP1A, MIPT3, ATF4/5 and NUDEL: regulation and loss of interaction with mutation.Hum. Mol. Genet. 2003; 12: 1591-1608Crossref PubMed Scopus (331) Google Scholar, Ozeki et al., 2003Ozeki Y. Tomoda T. Kleiderlein J. Kamiya A. Bord L. Fujii K. Okawa M. Yamada N. Hatten M.E. Snyder S.H. et al.Disrupted-in-Schizophrenia-1 (DISC-1): mutant truncation prevents binding to NudE-like (NUDEL) and inhibits neurite outgrowth.Proc. Natl. Acad. Sci. USA. 2003; 100: 289-294Crossref PubMed Scopus (342) Google Scholar). Knockdown of NDEL1 in newborn neurons in the adult hippocampus leads to primary defects in neuronal positioning and appearance of ectopic dendrites, representing some, but not all, of phenotypes observed with DISC1 suppression (Duan et al., 2007Duan X. Chang J.H. Ge S. Faulkner R.L. Kim J.Y. Kitabatake Y. Liu X.B. Yang C.H. Jordan J.D. Ma D.K. et al.Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain.Cell. 2007; 130: 1146-1158Abstract Full Text Full Text PDF PubMed Scopus (520) Google Scholar). 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., 2007Camargo L.M. Collura V. Rain J.C. Mizuguchi K. Hermjakob H. Kerrien S. Bonnert T.P. Whiting P.J. Brandon N.J. Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia.Mol. Psychiatry. 2007; 12: 74-86Crossref PubMed Scopus (352) Google Scholar). 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. Fasciculation and Elongation Protein Zeta-1 (FEZ1) is one of the first identified binding partners of DISC1 (Miyoshi et al., 2003Miyoshi K. Honda A. Baba K. Taniguchi M. Oono K. Fujita T. Kuroda S. Katayama T. Tohyama M. Disrupted-In-Schizophrenia 1, a candidate gene for schizophrenia, participates in neurite outgrowth.Mol. Psychiatry. 2003; 8: 685-694Crossref PubMed Scopus (261) Google Scholar). FEZ1 is a mammalian ortholog of the Caenorhabditis elegans UNC-76 protein, thought to be involved in nerve growth and fasciculation (Bloom and Horvitz, 1997Bloom L. Horvitz H.R. The Caenorhabditis elegans gene unc-76 and its human homologs define a new gene family involved in axonal outgrowth and fasciculation.Proc. Natl. Acad. Sci. USA. 1997; 94: 3414-3419Crossref PubMed Scopus (146) Google Scholar, Kuroda et al., 1999Kuroda S. Nakagawa N. Tokunaga C. Tatematsu K. Tanizawa K. Mammalian homologue of the Caenorhabditis elegans UNC-76 protein involved in axonal outgrowth is a protein kinase C zeta-interacting protein.J. Cell Biol. 1999; 144: 403-411Crossref PubMed Scopus (84) Google Scholar). FEZ1 expression is developmentally regulated and appears to be abundant in the adult mouse dentate gyrus (Miyoshi et al., 2003Miyoshi K. Honda A. Baba K. Taniguchi M. Oono K. Fujita T. Kuroda S. Katayama T. Tohyama M. Disrupted-In-Schizophrenia 1, a candidate gene for schizophrenia, participates in neurite outgrowth.Mol. Psychiatry. 2003; 8: 685-694Crossref PubMed Scopus (261) Google Scholar, Sakae et al., 2008Sakae N. Yamasaki N. Kitaichi K. Fukuda T. Yamada M. Yoshikawa H. Hiranita T. Tatsumi Y. Kira J. Yamamoto T. et al.Mice lacking the schizophrenia-associated protein FEZ1 manifest hyperactivity and enhanced responsiveness to psychostimulants.Hum. Mol. Genet. 2008; 17: 3191-3203Crossref PubMed Scopus (46) Google Scholar). In vitro, FEZ1 colocalizes with DISC1 at neuronal growth cones and regulates neurite outgrowth of PC12 cells (Miyoshi et al., 2003Miyoshi K. Honda A. Baba K. Taniguchi M. Oono K. Fujita T. Kuroda S. Katayama T. Tohyama M. Disrupted-In-Schizophrenia 1, a candidate gene for schizophrenia, participates in neurite outgrowth.Mol. Psychiatry. 2003; 8: 685-694Crossref PubMed Scopus (261) Google Scholar). 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 et al., 2008Sakae N. Yamasaki N. Kitaichi K. Fukuda T. Yamada M. Yoshikawa H. Hiranita T. Tatsumi Y. Kira J. Yamamoto T. et al.Mice lacking the schizophrenia-associated protein FEZ1 manifest hyperactivity and enhanced responsiveness to psychostimulants.Hum. Mol. Genet. 2008; 17: 3191-3203Crossref PubMed Scopus (46) Google Scholar), 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., 2004Yamada K. Nakamura K. Minabe Y. Iwayama-Shigeno Y. Takao H. Toyota T. Hattori E. Takei N. Sekine Y. Suzuki K. et al.Association analysis of FEZ1 variants with schizophrenia in Japanese cohorts.Biol. Psychiatry. 2004; 56: 683-690Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar), but not in others (Hodgkinson et al., 2007Hodgkinson C.A. Goldman D. Ducci F. DeRosse P. Caycedo D.A. Newman E.R. Kane J.M. Roy A. Malhotra A.K. The FEZ1 gene shows no association to schizophrenia in Caucasian or African American populations.Neuropsychopharmacology. 2007; 32: 190-196Crossref PubMed Scopus (15) Google Scholar, Koga et al., 2007Koga M. Ishiguro H. Horiuchi Y. Albalushi T. Inada T. Iwata N. Ozaki N. Ujike H. Muratake T. Someya T. Arinami T. Failure to confirm the association between the FEZ1 gene and schizophrenia in a Japanese population.Neurosci. Lett. 2007; 417: 326-329Crossref PubMed Scopus (13) Google Scholar, Nicodemus et al., 2010Nicodemus K.K. Callicott J.H. Higier R.G. Luna A. Nixon D.C. Lipska B.K. Vakkalanka R. Giegling I. Rujescu D. St Clair D. et al.Evidence of statistical epistasis between DISC1, CIT and NDEL1 impacting risk for schizophrenia: biological validation with functional neuroimaging.Hum. Genet. 2010; 127: 441-452Crossref PubMed Scopus (76) Google Scholar, Rastogi et al., 2009Rastogi A. Zai C. Likhodi O. Kennedy J.L. Wong A.H. Genetic association and post-mortem brain mRNA analysis of DISC1 and related genes in schizophrenia.Schizophr. Res. 2009; 114: 39-49Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar). 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., 2006Lipska B.K. Peters T. Hyde T.M. Halim N. Horowitz C. Mitkus S. Weickert C.S. Matsumoto M. Sawa A. Straub R.E. et al.Expression of Dros. Inf. Serv.C1 binding partners is reduced in schizophrenia and associated with Dros. Inf. Serv.C1 SNPs.Hum. Mol. Genet. 2006; 15: 1245-1258Crossref PubMed Scopus (143) Google Scholar). These findings raise the possibility that FEZ1 and DISC1 may cooperate to regulate both neuronal development and risk for schizophrenia. In the present study, we used adult mouse 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). We first examined their efficacy in knocking down the expression of endogenous FEZ1 in cultured adult mouse neural progenitors, which expressed FEZ1 during the proliferation state and after induced neuronal differentiation (see Figure S1A available online). Two shRNAs against mouse fez1 (shRNA-F1 and shRNA-F2), but not a control shRNA (shRNA-C1) (Ma et al., 2008Ma D.K. Chiang C.H. Ponnusamy K. Ming G.L. Song H. G9a and Jhdm2a regulate embryonic stem cell fusion-induced reprogramming of adult neural stem cells.Stem Cells. 2008; 26: 2131-2141Crossref PubMed Scopus (96) Google Scholar), were very effective in knocking down the expression of endogenous FEZ, but not DISC1 or NDEL1, at the protein level (Figure 1A ; Figure S1B). To assess the potential function of FEZ1 in regulating development of newborn neurons in the adult brain, we stereotaxically injected retroviruses coexpressing shRNA and GFP into the dentate gyrus of the adult mice brain. GFP+ newborn neurons were examined with confocal microscopy at 14 days postinjection (dpi). When compared with GFP+ neurons expressing shRNA-C1, there was a significant increase in the soma size of GFP+ neurons expressing either shRNA-F1 or shRNA-F2 (Figure 1B). Furthermore, GFP+ neurons expressing either shRNA-F1 or shRNA-F2 exhibited accelerated dendritic development with significant increases in both total dendritic length and complexity as shown by the Sholl analysis (Figures 1C–1E). Interestingly, increased dendritic growth and soma hypertrophy have also been observed with DISC1 knockdown in these newborn dentate granule cells in the adult hippocampus (Duan et al., 2007Duan X. Chang J.H. Ge S. Faulkner R.L. Kim J.Y. Kitabatake Y. Liu X.B. Yang C.H. Jordan J.D. Ma D.K. et al.Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain.Cell. 2007; 130: 1146-1158Abstract Full Text Full Text PDF PubMed Scopus (520) Google Scholar). On the other hand, GFP+ neurons with FEZ1 knockdown did not exhibit ectopic primary dendrites, aberrant neuronal positioning (Figure S1C), or mossy fiber axonal mistargeting (Figure S1D), other characteristic defects that result from DISC1 knockdown (Duan et al., 2007Duan X. Chang J.H. Ge S. Faulkner R.L. Kim J.Y. Kitabatake Y. Liu X.B. Yang C.H. Jordan J.D. Ma D.K. et al.Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain.Cell. 2007; 130: 1146-1158Abstract Full Text Full Text PDF PubMed Scopus (520) Google Scholar, Faulkner et al., 2008Faulkner R.L. Jang M.H. Liu X.B. Duan X. Sailor K.A. Kim J.Y. Ge S. Jones E.G. Ming G.L. Song H. Cheng H.J. Development of hippocampal mossy fiber synaptic outputs by new neurons in the adult brain.Proc. Natl. Acad. Sci. USA. 2008; 105: 14157-14162Crossref PubMed Scopus (171) Google Scholar, Kim et al., 2009Kim J.Y. Duan X. Liu C.Y. Jang M.H. Guo J.U. Pow-anpongkul N. Kang E. Song H. Ming G.L. DISC1 regulates new neuron development in the adult brain via modulation of AKT-mTOR signaling through KIAA1212.Neuron. 2009; 63: 761-773Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar). Thus, FEZ1 knockdown leads to a specific subset of, but not all, developmental defects observed in newborn neurons with DISC1 knockdown during adult neurogenesis. The similarity of phenotypes from two shRNAs against different regions of the fez1 gene suggests a specific role of FEZ1 in the development of newborn neurons in the adult brain. To further confirm the specificity of the shRNA manipulation, in vivo rescue experiments were performed. We engineered two sets of retroviruses: the first coexpressing GFP and wild-type (WT) mouse fez1 cDNA without the 3′ untranslated region (3′UTR; pCUXIE-mFEZ1), or GFP alone (pCUXIE); the second coexpressing mCherry and shRNA-F1 (Figure S2A). The shRNA-F1 targets the 3′UTR of the mouse fez1 gene, thus it does not affect mFEZ1 expression from the rescue vector (pCUXIE-mFEZ1). The two types of engineered retroviruses were coinjected into the adult dentate gyrus (Figure 2A ). Expression of shRNA-F1 and mCherry resulted in significant increases in the total dendritic length and soma size in comparison to those expressing shRNA-C1, whereas overexpression of mFEZ1 itself did not lead to any obvious effects (Figures 2B and 2C), except for a modest change in the dendritic complexity, but not the total dendritic length (Figure S2B). Importantly, coexpression of mFEZ1, but not vector control, largely normalized increased dendritic growth and soma hypertrophy by shRNA-F1 (Figures 2B and 2C). Under all conditions, no significant effects on the number of primary dendrites and neuronal positioning were detected (Figures S2D and S2E). Taken together, these rescue experiments further support specific roles of FEZ1 in regulating distinct aspects of new neuron development in the adult brain. The similar effect of DISC1 and FEZ1 knockdown on dendritic growth and soma size of newborn neurons in the adult brain and reported direct interaction between these two proteins (Miyoshi et al., 2003Miyoshi K. Honda A. Baba K. Taniguchi M. Oono K. Fujita T. Kuroda S. Katayama T. Tohyama M. Disrupted-In-Schizophrenia 1, a candidate gene for schizophrenia, participates in neurite outgrowth.Mol. Psychiatry. 2003; 8: 685-694Crossref PubMed Scopus (261) Google Scholar) suggest that they may functionally interact in regulating neuronal development. We previously generated a collection of shRNAs against mouse disc1 that exhibit different knockdown efficacy (Duan et al., 2007Duan X. Chang J.H. Ge S. Faulkner R.L. Kim J.Y. Kitabatake Y. Liu X.B. Yang C.H. Jordan J.D. Ma D.K. et al.Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain.Cell. 2007; 130: 1146-1158Abstract Full Text Full Text PDF PubMed Scopus (520) Google Scholar). Expression of the strong shRNA against disc1 (shRNA-D1) in newborn neurons led to the full spectrum of phenotypes at 14 dpi, whereas expression of the weak shRNA against disc1 (shRNA-D3) by itself led to a modest phenotype that manifests at 28 dpi, but not at 14 dpi (Figures 3A and 3C–3E ; Figures S3B and S3C) (Duan et al., 2007Duan X. Chang J.H. Ge S. Faulkner R.L. Kim J.Y. Kitabatake Y. Liu X.B. Yang C.H. Jordan J.D. Ma D.K. et al.Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain.Cell. 2007; 130: 1146-1158Abstract Full Text Full Text PDF PubMed Scopus (520) Google Scholar). To examine a potential interaction between FEZ1 and DISC1, we employed an in vivo double knockdown approach (Figure S3A). Interestingly, coexpression of shRNA-F1 and shRNA-D3 exacerbated the dendritic growth phenotype compared with expression of shRNA-F1 alone, as shown in both total dendritic length and complexity (Figures 3B–3D). On the other hand, no apparent synergistic effect was observed for soma size (Figure 3E), number of ectopic dendrites, or positioning of newborn neurons (Figures S3B and S3C). These results suggest that FEZ1 and DISC1 functionally interact to regulate dendritic development of newborn neurons in the adult brain. To further assess the interaction between endogenous DISC1 and FEZ1 in regulating neuronal development, we explored a blocking peptide using the DISC1 domain that interacts with FEZ1 (aa 446–633 of mouse DISC1; Figure S3D) (Miyoshi et al., 2003Miyoshi K. Honda A. Baba K. Taniguchi M. Oono K. Fujita T. Kuroda S. Katayama T. Tohyama M. Disrupted-In-Schizophrenia 1, a candidate gene for schizophrenia, participates in neurite outgrowth.Mol. Psychiatry. 2003; 8: 685-694Crossref PubMed Scopus (261) Google Scholar). In the coimmunoprecipitation (co-IP) analysis, expression of this peptide in HEK293 cells attenuated interaction between exogenous DISC1 and FEZ1, but not between DISC1 and endogenous KIAA1212/Girdin (Kim et al., 2009Kim J.Y. Duan X. Liu C.Y. Jang M.H. Guo J.U. Pow-anpongkul N. Kang E. Song H. Ming G.L. DISC1 regulates new neuron development in the adult brain via modulation of AKT-mTOR signaling through KIAA1212.Neuron. 2009; 63: 761-773Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar) or Kendrin (Shimizu et al., 2008Shimizu S. Matsuzaki S. Hattori T. Kumamoto N. Miyoshi K. Katayama T. Tohyama M. DISC1-kendrin interaction is involved in centrosomal microtubule network formation.Biochem. Biophys. Res. Commun. 2008; 377: 1051-1056Crossref PubMed Scopus (31) Google Scholar), two other proteins interacting with DISC1 at sites that overlap with this region (Figure S3D). Furthermore, overexpression of this peptide significantly reduced the interaction between endogenous DISC1 and FEZ1 in adult neural progenitors, but had no effect on the interaction between endogenous DISC1 and NDEL1 (Figure S3E), supporting the specificity of the blocking peptide on the DISC1 and FEZ1 interaction. Retrovirus-mediated coexpression of the DISC1 peptide and GFP in newborn neurons in the adult dentate gyrus led to increased total dendritic length and complexity as well as soma hypertrophy of GFP+ neurons at 14 dpi (Figures 3F–3H), but no effect on the number of primary dendrites or neuronal positioning (Figures S3F and S3G), fully recapitulating the FEZ1 knockdown phenotype. Taken together, these results support that FEZ1 regulates specific aspects of new neuron development in the adult brain through functional interaction with DISC1. NDEL1 is another DISC1 interacting protein that regulates neuronal development in vivo (Duan et al., 2007Duan X. Chang J.H. Ge S. Faulkner R.L. Kim J.Y. Kitabatake Y. Liu X.B. Yang C.H. Jordan J.D. Ma D.K. et al.Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain.Cell. 2007; 130: 1146-1158Abstract Full Text Full Text PDF PubMed Scopus (520) Google Scholar, Sasaki et al., 2005Sasaki S. Mori D. Toyo-oka K. Chen A. Garrett-Beal L. Muramatsu M. Miyagawa S. Hiraiwa N. Yoshiki A. Wynshaw-Boris A. Hirotsune S. Complete loss of Ndel1 results in neuronal migration defects and early embryonic lethality.Mol. Cell. Biol. 2005; 25: 7812-7827Crossref PubMed Scopus (142) Google Scholar, Shu et al., 2004Shu T. Ayala R. Nguyen M.D. Xie Z. Gleeson J.G. Tsai L.H. Ndel1 operates in a common pathway with LIS1 and cytoplasmic dynein to regulate cortical neuronal positioning.Neuron. 2004; 44: 263-277Abstract Full Text Full Text PDF PubMed Scopus (303) Google Scholar). Consistent with" @default.
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• W2095751946 cites W2014738505 @default.
• W2095751946 cites W2023060626 @default.
• W2095751946 cites W2032284123 @default.
• W2095751946 cites W2036538226 @default.
• W2095751946 cites W2041553887 @default.
• W2095751946 cites W2047679528 @default.
• W2095751946 cites W2049733177 @default.
• W2095751946 cites W2053196964 @default.
• W2095751946 cites W2057608998 @default.
• W2095751946 cites W2060387793 @default.
• W2095751946 cites W2066477949 @default.
• W2095751946 cites W2067961999 @default.
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