Hedgehog signaling controls mesenchymal growth in the developing mammalian digestive tract
Hedgehog signaling controls mesenchymal growth in the developing mammalian digestive tract
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DOI：
10.1242/dev.044586
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发表时间：
2010-05-15
期刊：
影响因子：
4.6
通讯作者：
McMahon, Andrew P.
中科院分区：
文献类型：
--
作者：
Mao, Junhao;Kim, Byeong-Moo;McMahon, Andrew P.
脊椎动物消化道的内稳态需要内胚层上皮和来自内脏中胚层的间充质细胞之间的相互作用。这两个组织层之间的信号传导对于发育中的肠道的形成和生长也至关重要。从早期发育阶段，音刺猬（Shh）和印度刺猬（Ihh）由哺乳动物肠道的内胚层分泌，表明发育作用。此外，失调的hedgehog（Hh）信号传导涉及先天性缺陷和由胃肠道引起的癌症。在小鼠中，只有有限的胃肠道异常后出现的Shh或Ihh的删除。然而，考虑到它们的内胚层表达结构域有相当大的重叠，这些信号之间的功能冗余可能掩盖了Hh信号在哺乳动物肠道发育中更广泛的作用。为了解决这种可能性，我们采用了一种有条件的方法，从早期小鼠肠道内胚层中去除Shh和Ihh功能。复合突变体的分析表明，连续的Hh信号传导对于肠管的区域图案化是不可或缺的，但对于底层间充质的生长是必不可少的。额外的体外分析，连同遗传获得功能的研究，进一步证明，Hh蛋白作为旁分泌有丝分裂原，以促进相邻的间充质祖细胞，包括那些平滑肌隔室的扩展。总之，这些研究为哺乳动物胃肠器官发生和疾病的组织相互作用提供了新的见解。
Homeostasis of the vertebrate digestive tract requires interactions between an endodermal epithelium and mesenchymal cells derived from the splanchnic mesoderm. Signaling between these two tissue layers is also crucial for patterning and growth of the developing gut. From early developmental stages, sonic hedgehog (Shh) and indian hedgehog (Ihh) are secreted by the endoderm of the mammalian gut, indicative of a developmental role. Further, misregulated hedgehog (Hh) signaling is implicated in both congenital defects and cancers arising from the gastrointestinal tract. In the mouse, only limited gastrointestinal anomalies arise following removal of either Shh or Ihh. However, given the considerable overlap in their endodermal expression domains, a functional redundancy between these signals might mask a more extensive role for Hh signaling in development of the mammalian gut. To address this possibility, we adopted a conditional approach to remove both Shh and Ihh functions from early mouse gut endoderm. Analysis of compound mutants indicates that continuous Hh signaling is dispensable for regional patterning of the gut tube, but is essential for growth of the underlying mesenchyme. Additional in vitro analysis, together with genetic gain-of-function studies, further demonstrate that Hh proteins act as paracrine mitogens to promote the expansion of adjacent mesenchymal progenitors, including those of the smooth muscle compartment. Together, these studies provide new insights into tissue interactions underlying mammalian gastrointestinal organogenesis and disease.