Alx4 relays sequential FGF signaling to induce lacrimal gland morphogenesis.
Alx4 relays sequential FGF signaling to induce lacrimal gland morphogenesis.
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DOI：
10.1371/journal.pgen.1007047
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发表时间：
2017-10
期刊：
影响因子：
4.5
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Garg A;Bansal M;Gotoh N;Feng GS;Zhong J;Wang F;Kariminejad A;Brooks S;Zhang X
信号通路的顺序使用对于引导多能祖细胞进入不同的细胞命运是必不可少的。在这里，我们表明，Shp 2专门介导FGF，但不是PDGF信号在神经嵴控制泪腺发育。除了防止p53非依赖性细胞凋亡和促进Sox 10表达神经嵴的迁移外，Shp 2还需要同源结构域转录因子Alx 4的表达，Alx 4直接控制泪腺诱导所必需的眼周间充质中Fgf 10的表达。我们发现，Alx 4结合FGF 10内含子元件保守的陆生动物，但不是水生动物，潜在的泪腺系统的进化出现在一个通风的环境。ALX 4/Alx 4的失活导致人和小鼠的泪腺发育不全。这些结果揭示了Alx 4在泪腺发育的神经嵴中介导FGF-Shp 2-FGF信号传导中的关键作用。泪腺发育不全引起的干眼病是最常见的眼部疾病之一。在这项研究中，我们表明，Shp 2介导的顺序使用的FGF信号在泪腺发育。我们的研究确定Alx 4作为Shp 2信号传导的新靶点和人类泪腺发育不全的致病基因。鉴于这一结果，Alx 4在引导多能干细胞产生泪腺组织方面也可能具有潜在作用。最后，我们的数据揭示了一个Alx 4-Fgf 10调控单元，它在从人类到爬行动物的各种陆生动物中广泛保守，但在两栖动物和鱼类等水生动物中却不保守，这揭示了泪腺是如何作为陆生动物的进化创新而出现的，以适应他们新发现的暴露于通风环境的。
The sequential use of signaling pathways is essential for the guidance of pluripotent progenitors into diverse cell fates. Here, we show that Shp2 exclusively mediates FGF but not PDGF signaling in the neural crest to control lacrimal gland development. In addition to preventing p53-independent apoptosis and promoting the migration of Sox10-expressing neural crests, Shp2 is also required for expression of the homeodomain transcription factor Alx4, which directly controls Fgf10 expression in the periocular mesenchyme that is necessary for lacrimal gland induction. We show that Alx4 binds an Fgf10 intronic element conserved in terrestrial but not aquatic animals, underlying the evolutionary emergence of the lacrimal gland system in response to an airy environment. Inactivation of ALX4/Alx4 causes lacrimal gland aplasia in both human and mouse. These results reveal a key role of Alx4 in mediating FGF-Shp2-FGF signaling in the neural crest for lacrimal gland development. The dry eye disease caused by lacrimal gland dysgenesis is one of the most common ocular ailments. In this study, we show that Shp2 mediates the sequential use of FGF signaling in lacrimal gland development. Our study identifies Alx4 as a novel target of Shp2 signaling and a causal gene for lacrimal gland aplasia in humans. Given this result, there may also be a potential role for Alx4 in guiding pluripotent stem cells to produce lacrimal gland tissue. Finally, our data reveals an Alx4-Fgf10 regulatory unit broadly conserved in the diverse array of terrestrial animals from humans to reptiles, but not in aquatic animals such as amphibians and fish, which sheds light on how the lacrimal gland arose as an evolutionary innovation of terrestrial animals to adapt to their newfound exposure to an airy environment.
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