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Endosome-Mediated Epithelial Remodeling Downstream of Hedgehog-Gli Is Required for Tracheoesophageal Separation.
Developmental Cell ( IF 10.7 ) Pub Date : 2019-12-05 , DOI: 10.1016/j.devcel.2019.11.003 Talia Nasr 1 , Pamela Mancini 2 , Scott A Rankin 2 , Nicole A Edwards 2 , Zachary N Agricola 3 , Alan P Kenny 3 , Jessica L Kinney 2 , Keziah Daniels 2 , Jon Vardanyan 2 , Lu Han 2 , Stephen L Trisno 1 , Sang-Wook Cha 2 , James M Wells 1 , Matthew J Kofron 1 , Aaron M Zorn 1
Developmental Cell ( IF 10.7 ) Pub Date : 2019-12-05 , DOI: 10.1016/j.devcel.2019.11.003 Talia Nasr 1 , Pamela Mancini 2 , Scott A Rankin 2 , Nicole A Edwards 2 , Zachary N Agricola 3 , Alan P Kenny 3 , Jessica L Kinney 2 , Keziah Daniels 2 , Jon Vardanyan 2 , Lu Han 2 , Stephen L Trisno 1 , Sang-Wook Cha 2 , James M Wells 1 , Matthew J Kofron 1 , Aaron M Zorn 1
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The trachea and esophagus arise from the separation of a common foregut tube during early fetal development. Mutations in key signaling pathways such as Hedgehog (HH)/Gli can disrupt tracheoesophageal (TE) morphogenesis and cause life-threatening birth defects (TEDs); however, the underlying cellular mechanisms are unknown. Here, we use mouse and Xenopus to define the HH/Gli-dependent processes orchestrating TE morphogenesis. We show that downstream of Gli the Foxf1+ splanchnic mesenchyme promotes medial constriction of the foregut at the boundary between the presumptive Sox2+ esophageal and Nkx2-1+ tracheal epithelium. We identify a unique boundary epithelium co-expressing Sox2 and Nkx2-1 that fuses to form a transient septum. Septum formation and resolution into distinct trachea and esophagus requires endosome-mediated epithelial remodeling involving the small GTPase Rab11 and localized extracellular matrix degradation. These are disrupted in Gli-deficient embryos. This work provides a new mechanistic framework for TE morphogenesis and informs the cellular basis of human TEDs.
中文翻译：
气管食管分离需要Hedgehog-Gli下游的内体介导的上皮重塑。
气管和食道是在胎儿早期发育过程中分离出一条共同的前肠管而引起的。刺猬（HH）/ Gli等关键信号通路的突变会破坏气管食管（TE）的形态发生，并危及生命。然而，潜在的细胞机制尚不清楚。在这里，我们使用小鼠和非洲爪蟾来定义编排TE形态发生的HH / Gli依赖过程。我们显示，Gli的下游Foxf1 +内脏间充质促进假定的Sox2 +食管和Nkx2-1 +气管上皮之间边界处的前肠内侧收缩。我们确定一个独特的边界上皮细胞共表达Sox2和Nkx2-1，融合形成瞬态隔膜。隔垫的形成和分解成独特的气管和食道需要内体介导的上皮重塑，其中涉及小的GTPase Rab11和局部细胞外基质降解。这些在缺乏Gli的胚胎中被破坏。这项工作为TE形态发生提供了一个新的机制框架，并为人类TEDs的细胞基础提供了信息。
更新日期：2019-12-05
中文翻译：
气管食管分离需要Hedgehog-Gli下游的内体介导的上皮重塑。
气管和食道是在胎儿早期发育过程中分离出一条共同的前肠管而引起的。刺猬（HH）/ Gli等关键信号通路的突变会破坏气管食管（TE）的形态发生，并危及生命。然而，潜在的细胞机制尚不清楚。在这里，我们使用小鼠和非洲爪蟾来定义编排TE形态发生的HH / Gli依赖过程。我们显示，Gli的下游Foxf1 +内脏间充质促进假定的Sox2 +食管和Nkx2-1 +气管上皮之间边界处的前肠内侧收缩。我们确定一个独特的边界上皮细胞共表达Sox2和Nkx2-1，融合形成瞬态隔膜。隔垫的形成和分解成独特的气管和食道需要内体介导的上皮重塑，其中涉及小的GTPase Rab11和局部细胞外基质降解。这些在缺乏Gli的胚胎中被破坏。这项工作为TE形态发生提供了一个新的机制框架，并为人类TEDs的细胞基础提供了信息。
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