Abstract
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.
Highlights
During middle and late gestation of the mouse, the T-box transcription factor (TF) TBX18 is expressed in a population of mesenchymal cells in the lower embryonic abdomen
Due to the known role of Tbx18 in smooth muscle formation, we examined the relationship between TBX18 expression and smooth muscle formation by evaluating alpha-Smooth Muscle Actin (SMA) antibody staining on sections adjacent to those stained for TBX18
This study provides the first evidence that Tbx18 is required for normal differentiation of the prostatic stroma and that it indirectly influences the organization, proliferative control, and cellular identity of prostate epithelium
Summary
During middle and late gestation of the mouse, the T-box transcription factor (TF) TBX18 is expressed in a population of mesenchymal cells in the lower embryonic abdomen. These cells contribute to the stromal layer of nearly every organ in the urogenital system but with differing affects in each of them [1]. Secreted SHH and WNT signals from the ureter epithelium maintain the proliferation and eventual differentiation of these Tbx18-positive condensing mesenchymal cells [3,4,5]. A still unknown signal acting downstream of Tbx in the mesenchyme, which normally reciprocates the proliferation signal to the ureter epithelium, fails to be activated. The consequent fluid build-up leads to a grotesque enlargement of both the ureters and kidneys in Tbx mutants [2,6]
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