| 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 that schizophrenia has a strong genetic component. Several genome-wide association studies (GWASs) of schizophrenia have 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 of schizophrenia susceptibility 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 of schizophrenia in a sample of 107 Jewish-Israeli families. We found one genome-wide significant association in the intron of the DOCK4 gene (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. Both DOCK4 and CEACAM21 are biologically reasonable candidate genes for schizophrenia although generalizability of the association of DOCK4 with schizophrenia should be investigated in further studies. In addition, gene-wide significant associations were found within three schizophrenia candidate genes: PGBD1, RELN and PRODH, replicating previously reported associations. By application of a family-based strategy to GWAS, our study revealed new schizophrenia susceptibility loci in the Jewish-Israeli population. |
| SCZ Keywords | schizophrenia |
| 2 | Mol. Biol. Cell 2013 May 24: 1602-13 |
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| PMID | 23536706 |
| Title | Rac GEF Dock4 interacts with cortactin to regulate dendritic spine formation. |
| Abstract | In neuronal development, dendritic spine formation 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, and schizophrenia. We previously showed that DOCK4 is expressed in hippocampal neurons. However, the functions of DOCK4 in hippocampal neurons and the underlying molecular mechanisms are poorly understood. Here we show that DOCK4 is 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 of DOCK4 reduces dendritic spine density, which is rescued by coexpression of shRNA-resistant wild-type DOCK4 but not by a GEF-deficient mutant of DOCK4 or a truncated mutant lacking the cortactin-binding region. On the other hand, knockdown of cortactin suppresses DOCK4-mediated spine formation. Taken together, the results show a novel and functionally important interaction between DOCK4 and cortactin for regulating dendritic spine formation via activation of Rac. |
| SCZ Keywords | schizophrenia |
| 3 | J. Biol. Chem. 2013 Jul 288: 20034-45 |
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| 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 and schizophrenia. Nonetheless, the neuronal function of DOCK4 is only beginning to be understood. Using mouse neuroblastoma (Neuro-2a) cells as a model, this study identifies that DOCK4 is 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 regulates the establishment of the axon-dendrite polarity and the arborization of dendrites, two critical processes during neural differentiation. Importantly, a microdeletion DOCK4 mutant 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 of DOCK4 is 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 of DOCK4 for neurite differentiation during early neuronal development. |
| SCZ Keywords | schizophrenia |