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.
Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America, 61801.|Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America, 61801.
C Chase
CC
Bolt
Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America, 61801.|Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America, 61801.
Soumya
S
Negi
Skaggs School of Pharmacy, Department of Medicine, and Department of Pharmacology, University of California San Diego, La Jolla, CA, United States of America, 92037.
Nuno
N
Guimarães-Camboa
Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America, 61801.|Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America, 61801.
Huimin
H
Zhang
Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America, 61801.|Illinois Informatics Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America, 61801.
Joseph M
JM
Troy
Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America, 61801.|Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America, 61801.
Xiaochen
X
Lu
Institut für Molekularbiologie, OE5250, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany.
Andreas
A
Kispert
Skaggs School of Pharmacy, Department of Medicine, and Department of Pharmacology, University of California San Diego, La Jolla, CA, United States of America, 92037.
Sylvia M
SM
Evans
Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America, 61801.|Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America, 61801.|Illinois Informatics Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America, 61801.
Lisa
L
Stubbs
D000483:Alleles; D000818:Animals; D002450:Cell Communication; D002454:Cell Differentiation; D049109:Cell Proliferation; D004543:Ejaculatory Ducts / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D004622:Embryo, Mammalian; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D008297:Male; D051379:Mice; D009130:Muscle, Smooth / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D038081:Organogenesis / Q000235:genetics; D011467:Prostate / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism* / Q000473:pathology; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000235:genetics*; D014513:Ureter / Q000254:growth & development / Q000378:metabolism / Q000473:pathology
D020825:T-Box Domain Proteins; C420983:Tbx18 protein, mouse