A role for Tbx18 in prostate development and adult prostate health

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DESCRIPTION (provided by applicant): The prostate arises from the urogenital sinus relatively late in mammalian development, with most of the growth and differentiation of the organ occurring after birth. Throughout prostate development and into adulthood, paracrine signals from the surrounding mesenchyme regulate the growth, differentiation, and maintenance of the prostate epithelium in response to androgens. In turn, the differentiated epithelium provides signals to regulate activities within th mesenchyme and a continuing, balanced cross-talk between mesenchymal and epithelial components is critical to maintenance of a healthy, functioning prostate throughout adult life. Significant progress has been made in identifying the signaling pathways involved in mesenchymal- epithelial (M-E) interactions in the prostate. However, relatively little is known of the network of transcription factors (TFs) that regulate the earliest stages of prostate development, or that serve to maintain a balance of cell types and signaling pathways in adults. Our preliminary studies identify the T-box protein, Tbx18, as a vital member of this prostate regulatory network, active in the urogenital mesenchyme from the earliest stages of prostate development and continuing to play an important role in prostate maintenance into adulthood. Tbx18 null mutants die at birth, complicating the analysis of phenotypes in late-developing tissues. However, we have identified a relatively long-lived regulatory mutation of Tbx18, called 12Gso, and our preliminary studies have revealed a striking prostate phenotype in these mice. Using siRNA knockdown and chromatin immunoprecipitation (ChIP) in mouse cell lines, we have identified direct regulatory targets of Tbx18, many of which play key roles in prostate development. However, nothing is known about the in vivo targets of the Tbx18 protein, or of the upstream TFs that control its complex pattern of developmental expression. The goals of this project are (1) to elucidate Tbx18 target genes in the developing prostate; (2) to identify regulatory elements and upstream TFs that control Tbx18 prostate expression; and (3) to further characterize the developmental time-course and cellular manifestations of prostate phenotypes in Tbx18 mutant mice, and to tie development of these phenotypes to interacting TFs and target genes. In pursuit of these goals, we will be aided by a collection of valuable mouse genetic and other tools that are already available in our laboratory, including transgenic reporters, a conditional null ("floxed") allele, the 12Gso regulatory mutant, and a custom Tbx18 antibody developed by our group. We hypothesize that Tbx18 is a critical missing link in a regulatory network that controls prostate development, appearing in the UGM at the earliest developmental stages and continuing to act in both stroma and epithelium in adults. ! PUBLIC HEALTH RELEVANCE: This project focuses on the role of the Tbx18 transcription factor gene in development and maintenance of a healthy, functioning prostate. Our preliminary data show that Tbx18 is expressed in prostate from the earliest developmental stage, and that the dysfunction of this gene leads to abnormal development of the gland. We will use a combination of mouse genetics and genomic approaches to examine this developmental function in further depth, and to provide a mechanistic context for Tbx18 function by identifying genes that interact with Tbx18 and control its expression during urogenital development.