Tbx18 Regulates the Differentiation of Periductal Smooth Muscle Stroma and the Maintenance of Epithelial Integrity in the Prostate

PLOS ONE, Dec 2019

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.

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Tbx18 Regulates the Differentiation of Periductal Smooth Muscle Stroma and the Maintenance of Epithelial Integrity in the Prostate

April Tbx18 Regulates the Differentiation of Periductal Smooth Muscle Stroma and the Maintenance of Epithelial Integrity in the Prostate C. Chase Bolt 0 1 2 Soumya Negi 0 1 2 Nuno Guimarães-Camboa 0 2 Huimin Zhang 0 1 2 Joseph M. Troy 0 2 Xiaochen Lu 0 1 2 Andreas Kispert 0 2 Sylvia M. Evans 0 2 Lisa Stubbs 0 1 2 0 DK095685 from the U.S. National Institute of Diabetes and Digestive and Kidney Disorders (awarded to L.S.). The production of the Tbx18flox, Tbx18Cre, and Tbx18GFP alleles was supported by U.S. NIH National Heart, Lung, and Blood Institute R01 grants HL123747, HL117649, and HL074066 (awarded to S.M.E). The funders had no role in study 1 Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America , 61801 , 2 Institute for Genomic Biology, University of Illinois at Urbana- Champaign, Urbana, Illinois, United States of America , 61801 , 3 Skaggs School of Pharmacy, Department of Medicine, and Department of Pharmacology, University of California San Diego, La Jolla, CA, United States of America , 92037 , 4 Illinois Informatics Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America , 61801, 5 Institut für Molekularbiologie, OE5250, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, D-30625 Hannover , Germany 2 Editor: Gregory S. Barsh, Stanford University School of Medicine , UNITED STATES 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. - OPEN ACCESS design, data collection and analysis, decision to publish, or preparation of the manuscript. Introduction 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 ]. In the ureter, Tbx18 is essential to the formation of a coordinated smooth muscle layer that can conduct urine from the kidney to the bladder. Beginning at embryonic day 11.5 (E11.5) Tbx18-expressing mesenchymal cells begin to coalesce around the nascent ureter epithelial duct [ 2 ]. Secreted SHH and WNT signals from the ureter epithelium maintain the proliferation and eventual differentiation of these Tbx18-positive condensing mesenchymal cells [ 3–5 ]. However, in the absence of Tbx18, the mesenchymal cells fail to respond to the epithelial signals and subsequently retire to a fibrocytic fate [ 2 ]. Consequently, a still unknown signal acting downstream of Tbx18 in the mesenchyme, which normally reciprocates the proliferation signal to the ureter epithelium, fails to be activated. Due to the loss of these interdependent signaling mechanisms, neither the ureter epithelium nor the stroma proliferate sufficiently resulting in a ureter of reduced length, thickness, and elasticity. The consequent fluid build-up leads to a grotesque enlargement of both the ureters and kidneys in Tbx18 mutants [ 2,6 ]. Toward the posterior end of the urogenital system, the prostate is an organ essential to male fertility that arises developmentally from the urogenital sinus (UGS) [ 7 ]. Beginning at E16.5, the urogenital sinus mesenchyme (UGS-M) begins differentiat (...truncated)


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C. Chase Bolt, Soumya Negi, Nuno Guimarães-Camboa, Huimin Zhang, Joseph M. Troy, Xiaochen Lu, Andreas Kispert, Sylvia M. Evans, Lisa Stubbs. Tbx18 Regulates the Differentiation of Periductal Smooth Muscle Stroma and the Maintenance of Epithelial Integrity in the Prostate, PLOS ONE, 2016, Volume 11, Issue 4, DOI: 10.1371/journal.pone.0154413