Control of stomach smooth muscle development and intestinal rotation by transcription factor BARX1.
Control of stomach smooth muscle development and intestinal rotation by transcription factor BARX1.
复制标题
DOI：
10.1016/j.ydbio.2015.05.024
复制
发表时间：
2015-09-01
影响因子：
2.7
通讯作者：
Shivdasani RA
中科院分区：
文献类型：
--
作者：
Jayewickreme CD;Shivdasani RA
同源结构域转录因子 BARX1 的多种功能包括胃上皮细胞的 Wnt 依赖性、非细胞自主规范、气管-支气管分隔以及脾原基的 Wnt 依赖性扩张。肠系膜和胃间充质中 Barx1 水平的严格时空调节表明还有其他作用。为了确定这些功能，我们迫使 BARX1 在 Bapx1 表达域（包括肠系膜和肠间质）中进行组成型表达，并进一步详细检查了 Barx1−/− 胚胎。转基因胚胎总是表现出肠截断和旋转不良，部分反映了异常的左右模式。异位 BARX1 表达不影响肠上皮，但肠平滑肌发育具有胃壁的典型特征。 BARX1通常仅限于发育中的胃，通过促进肌源性祖细胞的增殖（以其他上皮下细胞为代价）来驱动该器官中平滑肌的强劲扩张。未分化的胚胎胃和肠间充质在 mRNA 表达方面表现出适度的差异，并且 BARX1 足以诱导肠细胞中的大部分胃特征。然而，在顺式调控位点的有限结合意味着 BARX1 可能主要通过其他转录因子发挥作用。在 BARX1+ 肠间质中异位表达并在 Barx1−/− 胃间质中减少的基因包括 Isl1、Pitx1、Six2 和 Pitx2，这些转录因子已知控制左右模式并影响平滑肌发育。总的证据表明，BARX1 在肠道旋转和胃肌生成中的强大功能是通过这一小组中间转录因子发生的。
Diverse functions of the homeodomain transcription factor BARX1 include Wnt-dependent, non-cell autonomous specification of the stomach epithelium, tracheo-bronchial septation, and Wnt-independent expansion of the spleen primordium. Tight spatio-temporal regulation of Barx1 levels in the mesentery and stomach mesenchyme suggests additional roles. To determine these functions, we forced constitutive BARX1 expression in the Bapx1 expression domain, which includes the mesentery and intestinal mesenchyme, and also examined Barx1−/− embryos in further detail. Transgenic embryos invariably showed intestinal truncation and malrotation, in part reflecting abnormal left-right patterning. Ectopic BARX1 expression did not affect intestinal epithelium, but intestinal smooth muscle developed with features typical of the stomach wall. BARX1, which is normally restricted to the developing stomach, drives robust smooth muscle expansion in this organ by promoting proliferation of myogenic progenitors at the expense of other sub-epithelial cells. Undifferentiated embryonic stomach and intestinal mesenchyme showed modest differences in mRNA expression and BARX1 was sufficient to induce much of the stomach profile in intestinal cells. However, limited binding at cis-regulatory sites implies that BARX1 may act principally through other transcription factors. Genes expressed ectopically in BARX1+ intestinal mesenchyme and reduced in Barx1−/− stomach mesenchyme include Isl1, Pitx1, Six2 and Pitx2, transcription factors known to control left-right patterning and influence smooth muscle development. The sum of evidence suggests that potent BARX1 functions in intestinal rotation and stomach myogenesis occur through this small group of intermediary transcription factors.