| 1 | Int. J. Neuropsychopharmacol. 2012 May 15: 459-69 |
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| PMID | 21682944 |
| Title | DOCK4 and CEACAM21 as novel schizophrenia candidate genes in the Jewish population. |
| Abstract | It is well accepted thatschizophreniahas a strong genetic component. Several genome-wide association studies (GWASs) ofschizophreniahave been published in recent years; most of them population based with a case-control design. Nevertheless, identifying the specific genetic variants which contribute to susceptibility to the disorder remains a challenging task. A family-based GWAS strategy may be helpful in the identification ofschizophreniasusceptibility genes since it is protected against population stratification, enables better accounting for genotyping errors and is more sensitive for identification of rare variants which have a very low frequency in the general population. In this project we implemented a family-based GWAS ofschizophreniain a sample of 107 Jewish-Israeli families. We found one genome-wide significant association in the intron of theDOCK4gene (rs2074127, p value=1.134�10??) and six additional nominally significant association signals with p<1�10??. One of the top single nucleotide polymorphisms (p<1�10??) which is located in the predicted intron of the CEACAM21 gene was significantly replicated in independent family-based sample of Arab-Israeli origin (rs4803480: p value=0.002; combined p value=9.61�10??), surviving correction for multiple testing. BothDOCK4and CEACAM21 are biologically reasonable candidate genes forschizophreniaalthough generalizability of the association ofDOCK4withschizophreniashould be investigated in further studies. In addition, gene-wide significant associations were found within threeschizophreniacandidate genes: PGBD1, RELN and PRODH, replicating previously reported associations. By application of a family-based strategy to GWAS, our study revealed newschizophreniasusceptibility loci in the Jewish-Israeli population. |
| SCZ Keywords | schizophrenia |
| 2 | Mol. Biol. Cell 2013 May 24: 1602-13 |
| PMID | 23536706 |
| Title | Rac GEF Dock4 interacts with cortactin to regulate dendritic spine formation. |
| Abstract | 在神经系统发育,树突棘形成is important for the establishment of excitatory synaptic connectivity and functional neural circuits. Developmental deficiency in spine formation results in multiple neuropsychiatric disorders.DOCK4, a guanine nucleotide exchange factor (GEF) for Rac, has been reported as a candidate genetic risk factor for autism, dyslexia, andschizophrenia. We previously showed thatDOCK4is expressed in hippocampal neurons. However, the functions ofDOCK4in hippocampal neurons and the underlying molecular mechanisms are poorly understood. Here we show thatDOCK4is highly concentrated in dendritic spines and implicated in spine formation via interaction with the actin-binding protein cortactin. In cultured neurons, short hairpin RNA (shRNA)-mediated knockdown ofDOCK4reduces dendritic spine density, which is rescued by coexpression of shRNA-resistant wild-typeDOCK4but not by a GEF-deficient mutant ofDOCK4or a truncated mutant lacking the cortactin-binding region. On the other hand, knockdown of cortactin suppressesDOCK4-mediated spine formation. Taken together, the results show a novel and functionally important interaction betweenDOCK4and cortactin for regulating dendritic spine formation via activation of Rac. |
| SCZ Keywords | schizophrenia |
| 3 | J. Biol. Chem. 2013 Jul 288: 20034-45 |
| PMID | 23720743 |
| Title | The atypical guanine nucleotide exchange factor Dock4 regulates neurite differentiation through modulation of Rac1 GTPase and actin dynamics. |
| Abstract | Precise regulation of neurite growth and differentiation determines accurate formation of synaptic connections, whose disruptions are frequently associated with neurological disorders. Dedicator of cytokinesis 4 (DOCK4), an atypical guanine nucleotide exchange factor for Rac1, is found to be associated with neuropsychiatric diseases, including autism andschizophrenia. Nonetheless, the neuronal function ofDOCK4is only beginning to be understood. Using mouse neuroblastoma (Neuro-2a) cells as a model, this study identifies thatDOCK4is critical for neurite differentiation and extension. This regulation is through activation of Rac1 and modulation of the dynamics of actin-enriched protrusions on the neurites. In cultured hippocampal neurons,DOCK4调节axon-dendrite p的建立olarity and the arborization of dendrites, two critical processes during neural differentiation. Importantly, a microdeletionDOCK4mutant linked to autism and dyslexia that lacks the GEF domain leads to defective neurite outgrowth and neuronal polarization. Further analysis reveals that the SH3 domain-mediated interaction ofDOCK4is required for its activity toward neurite differentiation, whereas its proline-rich C terminus is not essential for this regulation. Together, our findings reveal an important role ofDOCK4for neurite differentiation during early neuronal development. |
| SCZ Keywords | schizophrenia |