RESUMO
Copy-number variants of chromosome 16 region 16p11.2 are linked to neuropsychiatric disorders and are among the most prevalent in autism spectrum disorders. Of many 16p11.2 genes, Kctd13 has been implicated as a major driver of neurodevelopmental phenotypes. The function of KCTD13 in the mammalian brain, however, remains unknown. Here we delete the Kctd13 gene in mice and demonstrate reduced synaptic transmission. Reduced synaptic transmission correlates with increased levels of Ras homolog gene family, member A (RhoA), a KCTD13/CUL3 ubiquitin ligase substrate, and is reversed by RhoA inhibition, suggesting increased RhoA as an important mechanism. In contrast to a previous knockdown study, deletion of Kctd13 or kctd13 does not increase brain size or neurogenesis in mice or zebrafish, respectively. These findings implicate Kctd13 in the regulation of neuronal function relevant to neuropsychiatric disorders and clarify the role of Kctd13 in neurogenesis and brain size. Our data also reveal a potential role for RhoA as a therapeutic target in disorders associated with KCTD13 deletion.
Assuntos
Encéfalo/metabolismo , Proteínas de Transporte/metabolismo , Deleção de Genes , Transmissão Sináptica/genética , Proteínas de Peixe-Zebra/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo , Animais , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/psicologia , Transtorno Autístico/genética , Transtorno Autístico/psicologia , Encéfalo/anatomia & histologia , Encéfalo/citologia , Encéfalo/patologia , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/patologia , Proteínas de Transporte/genética , Deleção Cromossômica , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/psicologia , Cromossomos Humanos Par 16/genética , Proteínas Culina/metabolismo , Feminino , Deficiência Intelectual/genética , Deficiência Intelectual/psicologia , Masculino , Camundongos , Herança Multifatorial/genética , Neurogênese/genética , Tamanho do Órgão/genética , Reprodutibilidade dos Testes , Transmissão Sináptica/efeitos dos fármacos , Complexos Ubiquitina-Proteína Ligase , Peixe-Zebra , Proteínas de Peixe-Zebra/genética , Proteínas rho de Ligação ao GTP/antagonistas & inibidores , Proteína rhoA de Ligação ao GTPRESUMO
In 1993, the National Institutes of Health issued a mandate that funded research must include participation by racial and ethnic minority groups, and researchers were required to include in their proposals strategies by which they would achieve diversity in their samples. A methodological search for randomized clinical trials of panic disorder was conducted to evaluate ethnoracial differences in panic disorder symptoms, rates of minority inclusion in North American studies, and effective methods of minority recruitment. Less than half of the studies identified reported ethnic and racial data for their sample. Of the 21 studies that did report this information (n=2687), 82.7% were European American/non-Hispanic White, 4.9% were African American/Black, 3.4% were Hispanic, 1.1% were Asian American, and 1.4% were another ethnicity. The remaining 6.5% was simply classified as other/non-White. The primary recruitment techniques utilized were clinical referral and advertising, but neither of these methods were correlated with improved minority participation, nor was the number of recruitment sites. As minorities are greatly underrepresented in panic disorder studies, reported treatment outcomes may not generalize to all ethnic and cultural groups. Researchers have not followed NIH guidelines regarding inclusion of special populations. Inclusion of minorities in future studies is needed to fully understand issues related to the treatment of panic disorder in non-White populations. Suggestions for improved recruitment of ethnoracial minorities are discussed.
