Independent functions and mechanisms for homeobox gene Barx1 in patterning mouse stomach and spleen
Independent functions and mechanisms for homeobox gene Barx1 in patterning mouse stomach and spleen
复制标题
DOI：
10.1242/dev.009308
复制
发表时间：
2007-10-15
期刊：
影响因子：
4.6
通讯作者：
Shivdasani, Ramesh A.
中科院分区：
文献类型：
--
作者：
Kim, Byeong-Moo;Miletich, Isabelle;Shivdasani, Ramesh A.
同源异型盒基因在胚胎中传递位置信息，它们在哺乳动物肠道模式中的作用是一个相当感兴趣的话题。Barx 1在胎儿胃间充质中选择性表达并指导上覆内胚层的分化。重组组织培养物和年轻小鼠胚胎的研究先前表明，Barx 1控制分泌的Wnt拮抗剂的表达，抑制内胚层Wnt信号传导，使胃上皮分化。我们克服了Barx 1（-/ -）小鼠胚胎的妊娠中期致死性，并在此报告了一种独特的、前所未有的胃肠道同源异型转化模型中的异常谱。使用各种小鼠模型，我们证实了减弱Wnt信号在胃发育中的重要性以及Barx 1在抑制内胚层Wnt活性中的作用。缺乏Barx 1也会导致脾脏定位和扩张的完全渗透缺陷，脾脏是一个起源于胃间皮内层的器官。Barx 1在脾脏原基中不存在，但在胃系膜中高度表达，表明对脾脏发育有间接影响。然而，我们的研究结果反对Wnt拮抗作用在脾脏的发生中的作用。小鼠脾脏发育依赖于在脾脏原基中表达的几种同源结构域转录调节因子。Barx 1的缺失不影响这些基因中任何一个的表达，但显著降低了Wt 1的表达，Wt 1是一种与脾形态发生有关并在间皮中表达的转录因子。这些观察将Barx 1近端放置在脾脏发育的Wt 1途径中，并揭示了同源异型调节因子如何采用不同的分子机制来塑造邻近器官。
Homeobox genes convey positional information in embryos and their role in patterning the mammalian gut is a topic of considerable interest. Barx1 is expressed selectively in fetal stomach mesenchyme and directs differentiation of overlying endoderm. Recombinant tissue cultures and study of young mouse embryos previously suggested that Barx1 controls expression of secreted Wnt antagonists, which suppress endodermal Wnt signaling, to enable stomach epithelial differentiation. We overcame mid- gestational lethality of Barx1(-/ -) mouse embryos and report here the spectrum of anomalies in a distinctive and unprecedented model of gastrointestinal homeotic transformation. Using various mouse models, we confirm the importance of attenuated Wnt signaling in stomach development and the role of Barx1 in suppressing endodermal Wnt activity. Absence of Barx1 also results in fully penetrant defects in positioning and expansion of the spleen, an organ that originates within the mesothelial lining of the stomach. Barx1 is absent from the spleen primordium but highly expressed in the mesogastrium, indicating an indirect effect on spleen development. However, our results argue against a role for Wnt antagonism in genesis of the spleen. Mouse spleen development relies on several homeodomain transcriptional regulators that are expressed in the spleen primordium. Loss of Barx1 does not affect expression of any of these genes but notably reduces expression of Wt1, a transcription factor implicated in spleen morphogenesis and expressed in the mesothelium. These observations place Barx1 proximally within a Wt1 pathway of spleen development and reveal how a homeotic regulator employs different molecular mechanisms to mold neighboring organs.