RESUMO
The mammalian urogenital sinus (UGS) develops in a sex specific manner, giving rise to the prostate in the male and the sinus vagina in the embryonic female. Androgens, produced by the embryonic testis, have been shown to be crucial to this process. In this study we show that retinoic acid signaling is required for the initial stages of bud development from the male UGS. Enzymes involved in retinoic acid synthesis are expressed in the UGS mesenchyme in a sex specific manner and addition of ligand to female tissue is able to induce prostate-like bud formation in the absence of androgens, albeit at reduced potency. Functional studies in mouse organ cultures that faithfully reproduce the initiation of prostate development indicate that one of the roles of retinoic acid signaling in the male is to inhibit the expression of Inhba, which encodes the ßA subunit of Activin, in the UGS mesenchyme. Through in vivo genetic analysis and culture studies we show that inhibition of Activin signaling in the female UGS leads to a similar phenotype to that of retinoic acid treatment, namely bud formation in the absence of androgens. Our data also reveals that both androgens and retinoic acid have extra independent roles to that of repressing Activin signaling in the development of the prostate during fetal stages. This study identifies a novel role for retinoic acid as a mesenchymal factor that acts together with androgens to determine the position and initiation of bud development in the male UGS epithelia.
Assuntos
Ativinas/metabolismo , Organogênese/fisiologia , Transdução de Sinais/fisiologia , Tretinoína/metabolismo , Sistema Urogenital/embriologia , Ativinas/antagonistas & inibidores , Animais , Primers do DNA , Feminino , Imuno-Histoquímica , Hibridização In Situ , Subunidades beta de Inibinas/antagonistas & inibidores , Masculino , Camundongos , Próstata/embriologia , Reação em Cadeia da Polimerase em Tempo Real , Fatores Sexuais , Tretinoína/farmacologia , Sistema Urogenital/metabolismo , beta-GalactosidaseRESUMO
There is evidence that a substantial part of genetic predisposition to prostate cancer (PCa) may be due to lower penetrance genes which are found by genome-wide association studies. We have recently conducted such a study and seven new regions of the genome linked to PCa risk have been identified. Three of these loci contain candidate susceptibility genes: MSMB, LMTK2 and KLK2/3. The MSMB and KLK2/3 genes may be useful for PCa screening, and the LMTK2 gene might provide a potential therapeutic target. Together with results from other groups, there are now 23 germline genetic variants which have been reported. These results have the potential to be developed into a genetic test. However, we consider that marketing of tests to the public is premature, as PCa risk can not be evaluated fully at this stage and the appropriate screening protocols need to be developed. Follow-up validation studies, as well as studies to explore the psychological implications of genetic profile testing, will be vital prior to roll out into healthcare.
Assuntos
Predisposição Genética para Doença/genética , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/genética , Testes Genéticos , Humanos , Calicreínas/genética , Masculino , Proteínas de Membrana/genética , Proteínas Secretadas pela Próstata/genética , Proteínas Serina-Treonina Quinases/genética , Fatores de RiscoRESUMO
Prostate cancer is the most common cancer affecting males in developed countries. It shows consistent evidence of familial aggregation, but the causes of this aggregation are mostly unknown. To identify common alleles associated with prostate cancer risk, we conducted a genome-wide association study (GWAS) using blood DNA samples from 1,854 individuals with clinically detected prostate cancer diagnosed at
