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

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.

ORGANISM(S): Mus musculus

PROVIDER: GSE80083 | GEO | 2016/04/26

SECONDARY ACCESSION(S): PRJNA317775

REPOSITORIES: GEO

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Project description:Studies centered at the intersection of embryogenesis and carcinogenesis have identified striking parallels involving signaling pathways that modulate both developmental and neoplastic processes. In the prostate, reciprocal interactions between epithelium and stroma are known to influence neoplasia and also exert morphogenic effects via the urogenital sinus mesenchyme. In this study, we sought to determine molecular relationships between aspects of normal prostate development and prostate carcinogenesis. We first characterized the gene expression program associated with key points of murine prostate organogenesis spanning the initial in utero induction of prostate budding through maturity. We identified a highly reproducible temporal program of gene expression that partitioned according to the broad developmental stages of prostate induction, branching morphogenesis, and secretory differentiation. Comparisons of gene expression profiles of murine prostate cancers arising in the context of genetically engineered alterations in the Pten tumor suppressor and Myc oncogene identified significant associations between the profile of branching morphogenesis and both cancer models. Further, the expression of genes comprising the branching morphogenesis program, such as PRDX4, SLC43A1, and DNMT3A, was significantly altered in human neoplastic prostate epithelium. These results indicate that components of normal developmental processes are active in prostate neoplasia and provide further rationale for exploiting molecular features of organogenesis to understand cancer phenotypes. Whole male UGS (E14.5, E15.5, E16.5, and E17.5) or separated prostate lobes (P7, P30, and DP90) were dissected from C57BL6/J mice and snap frozen in liquid nitrogen. For each biological replication, we pooled 3 to 10 mice representing one or two litters. RNA from pools of UGS or specific prostate lobes (vp, ap, and dlp) was prepared using the Qiagen RNeasy Mini kit. We included an on-column DNaseI treatment to remove contaminating DNA. Before RNA amplification, we combined equal quantities of RNA from vp, ap, and dlp for the postnatal prostate samples. We amplified 1 ug of total RNA from each sample through one round using the Arcturus RiboAmp kit. For the E14.5 UGS reference sample, a second round of amplification was done to provide enough RNA for all microarrays. Each developmental sample was hybridized against the E14.5 UGS reference sample with a dye swap, for a total of 42 arrays. Warning: the normalized data for this study which was made public on December 1, 2009, was swapped for some samples. All normalized data has now been corrected as of February 25, 2010. Raw data was not affected.

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

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