Tbx18 Regulates the Differentiation of Periductal Smooth Muscle Stroma and the Maintenance of Epithelial Integrity in the Prostate.
Tbx18 Regulates the Differentiation of Periductal Smooth Muscle Stroma and the Maintenance of Epithelial Integrity in the Prostate.
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DOI：
10.1371/journal.pone.0154413
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Stubbs L
中科院分区：
文献类型：
--
作者：
Bolt CC;Negi S;Guimarães-Camboa N;Zhang H;Troy JM;Lu X;Kispert A;Evans SM;Stubbs L
T-box转录因子TBX 18对于几种组织中的间充质细胞分化是必不可少的，并且TBX 18功能丧失导致显著的器官畸形和围产期死亡。在这里，我们首次证明了Tbx 18是前列腺，特别是前叶中导管周围平滑肌基质细胞正常发育所必需的，对成年小鼠的前列腺健康有明显影响。前列腺异常仅在出生时Tbx 18突变体中微妙地明显;为了检查出生后前列腺发育，我们利用了相对长寿的亚型突变体和新的条件性Tbx 18等位基因。与输尿管相似，不能表达Tbx 18的细胞不能正常地凝聚成导管周围前列腺基质的平滑肌细胞。然而，与输尿管相反，突变型前列腺的导管周围基质细胞呈肥大的肌纤维母细胞状态，邻近上皮细胞变得严重紊乱。为了确定这种病理发生前的分子事件，我们比较了Tbx 18-null和野生型同窝仔在两个胚胎阶段的尿生殖窦（UGS）中的基因表达，前列腺从UGS发育。调节细胞增殖，平滑肌分化，前列腺上皮发育和炎症反应的基因在突变型尿生殖窦中显著失调，大约在Tbx 18首次在野生型UGS中表达的时候，这表明在调节这些基因中的直接作用。总之，这些结果表明，Tbx 18是必不可少的前列腺尿道周围间充质的分化和维护，它间接调节上皮细胞分化通过控制基质上皮信号。
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.