A Retinoic Acid-Hedgehog Cascade Coordinates Mesoderm-Inducing Signals and Endoderm Competence during Lung Specification.
A Retinoic Acid-Hedgehog Cascade Coordinates Mesoderm-Inducing Signals and Endoderm Competence during Lung Specification.
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DOI：
10.1016/j.celrep.2016.05.060
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发表时间：
2016-06-28
期刊：
影响因子：
8.8
通讯作者：
Zorn AM
中科院分区：
文献类型：
--
作者：
Rankin SA;Han L;McCracken KW;Kenny AP;Anglin CT;Grigg EA;Crawford CM;Wells JM;Shannon JM;Zorn AM
气管和肺的器官发生需要一系列复杂的中胚层-内胚层相互作用，这些相互作用由WNT、BMP、维甲酸（RA）和刺猬（Hh）介导，但这些途径如何在基因调控网络中相互作用尚不清楚。使用非洲爪蟾胚胎学，小鼠遗传学，和人类ES细胞培养，我们确定了一个保守的信号级联，启动呼吸谱系规范。我们发现，RA有多种作用，首先RA预图案的侧板中胚层，然后它促进Hh配体的表达在前肠内胚层。Hh随后向预图案化的中胚层发出信号以促进肺诱导配体Wnt 2/2b和Bmp 4的表达。最后，RA调节内胚层的能力以响应于这些中胚层WNT和BMP信号而激活Nkx 2 -1+呼吸程序。这些数据提供了对早期肺发育的见解，以及在器官发生过程中间充质信号如何与上皮能力协调的范例。控制呼吸上皮特化的调节网络知之甚少。兰金等人发现，进化上保守的RA-Hh信号级联对于呼吸特化是必需的，并且协调中胚层中肺诱导Wnt 2/2b配体的表达与内胚层应答能力。
Organogenesis of the trachea and lungs requires a complex series of mesoderm-endoderm interactions mediated by WNT, BMP, retinoic acid (RA) and hedgehog (Hh), but how these pathways interact in a gene regulatory network is less clear. Using Xenopus embryology, mouse genetics, and human ES cell cultures we identified a conserved signaling cascade that initiates respiratory lineage specification. We show that RA has multiple roles; first RA pre-patterns the lateral plate mesoderm and then it promotes Hh ligand expression in the foregut endoderm. Hh subsequently signals back to the pre-patterned mesoderm to promote expression of the lung-inducing ligands Wnt2/2b and Bmp4. Finally, RA regulates the competence of the endoderm to activate the Nkx2-1+ respiratory program in response to these mesodermal WNT and BMP signals. These data provide insights into early lung development and a paradigm for how mesenchymal signals are coordinated with epithelial competence during organogenesis. The regulatory network controlling respiratory epithelium specification is poorly understood. Rankin et al. find that an evolutionarily conserved RA-Hh signaling cascade is essential for respiratory specification, and coordinates expression of lung-inducing Wnt2/2b ligands in the mesoderm with endodermal competence to respond.