TBX18 regulates the differentiation of periductal smooth muscle stroma and the maintenance of epithelial integrity in the prostate

The T-box transcription factor TBX18 is essential to mesenchymal cell differentiation in several tissues and Tbx18 loss-of-function results in dramatic organ malformations and perinatal lethality. Here we demonstrate for the first time that Tbx18 is required for the normal development of periductal smooth muscle stromal cells in prostate, particularly in the anterior lobe, with a clear impact on prostate health in adult mice. Prostate abnormalities are only subtly apparent in Tbx18 mutants at birth; to examine postnatal prostate development we utilized a relatively long-lived hypomorphic mutant and a novel conditional Tbx18 allele. Similar to the ureter, cells that fail to express Tbx18 do not condense normally into smooth muscle cells of the periductal prostatic stroma. However, in contrast to ureter, the periductal stromal cells in mutant prostate assume a hypertrophic, myofibroblastic state and the adjacent epithelium becomes grossly disorganized. To identify molecular events preceding the onset of this pathology, we compared gene expression in the urogenital sinus (UGS), from which the prostate develops, in Tbx18-null and wild type littermates at two embryonic stages. Genes that regulate cell proliferation, smooth muscle differentiation, prostate epithelium development, and inflammatory response were significantly dysregulated in the mutant urogenital sinus around the time that Tbx18 is first expressed in the wild type UGS, suggesting a direct role in regulating those genes. Together, these results argue that Tbx18 is essential to the differentiation and maintenance of the prostate periurethral mesenchyme and that it indirectly regulates epithelial differentiation through control of stromal-epithelial signaling. Overall design: Embryos were collected from timed matings of Tbx18Gfp/+ knock-in mutants at E16.5 and E18.5, and genotyped to identify Tbx18Gfp/Gfp null mutants and wild-type (WT) littermates. The urogenital sinus (UGS) was dissected and used to extract RNA from each of three animals of each genotype. The RNA samples were pooled to generate libraries for sequencing.

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Bolt CC, Negi S, Guimarães-Camboa N, Zhang H, Troy JM, Lu X, Kispert A, Evans SM, Stubbs L