原发性纤毛对气管食管分隔至关重要。

IF 2 3区 生物学 Q2 ANATOMY & MORPHOLOGY
Lindsey Avery Fitzsimons, Evangelia Tasouri, Marc August Willaredt, Daniel Stetson, Christian Gojak, Joachim Kirsch, Humphrey A. R. Gardner, Karin Gorgas, Kerry L. Tucker
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引用次数: 0

摘要

引言:在哺乳动物发育过程中,初级纤毛在各种器官的模式形成和形态发生中发挥着关键作用。在这里,我们检测了鹅卵石突变体中的小鼠前肠分隔,鹅卵石突变体是编码鞭毛内转运蛋白IFT88的基因的低形态等位基因,IFT88是正常纤毛功能所必需的蛋白质。结果:我们揭示了初级纤毛在前肠分裂中的关键作用,因为它们在突变胚胎的前肠内胚层和间充质中的纤毛急剧减少导致了近端气管食管分隔缺陷和远端气管(支气管)食管瘘的形成,类似于人类最常见的先天性气管食管畸形。有趣的是,决定背消化和腹侧呼吸内胚层的背腔模式保持完整,而Hedgehog信号异常激活。结论:我们的研究结果表明,鹅卵石突变体代表了极少数既表现出正确的内胚层背腔规格,又表现出近端前肠区隔缺陷的小鼠模型之一。它是气管食管纤毛病的典范,为阐明原发纤毛如何协调分隔过程的分子机制提供了可能性。在鹅卵石胚胎中观察到的大量畸形使我们能够更深入地了解原发纤毛与人类VATER/VACTERL综合征之间的假定联系。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Primary cilia are critical for tracheoesophageal septation

Introduction

Primary cilia play pivotal roles in the patterning and morphogenesis of a wide variety of organs during mammalian development. Here we examined murine foregut septation in the cobblestone mutant, a hypomorphic allele of the gene encoding the intraflagellar transport protein IFT88, a protein essential for normal cilia function.

Results

We reveal a crucial role for primary cilia in foregut division, since their dramatic decrease in cilia in both the foregut endoderm and mesenchyme of mutant embryos resulted in a proximal tracheoesophageal septation defects and in the formation of distal tracheo(broncho)esophageal fistulae similar to the most common congenital tracheoesophageal malformations in humans. Interestingly, the dorsoventral patterning determining the dorsal digestive and the ventral respiratory endoderm remained intact, whereas Hedgehog signaling was aberrantly activated.

Conclusions

Our results demonstrate the cobblestone mutant to represent one of the very few mouse models that display both correct endodermal dorsoventral specification but defective compartmentalization of the proximal foregut. It stands exemplary for a tracheoesophageal ciliopathy, offering the possibility to elucidate the molecular mechanisms how primary cilia orchestrate the septation process. The plethora of malformations observed in the cobblestone embryo allow for a deeper insight into a putative link between primary cilia and human VATER/VACTERL syndromes.

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来源期刊
Developmental Dynamics
Developmental Dynamics 生物-发育生物学
CiteScore
5.10
自引率
8.00%
发文量
116
审稿时长
3-8 weeks
期刊介绍: Developmental Dynamics, is an official publication of the American Association for Anatomy. This peer reviewed journal provides an international forum for publishing novel discoveries, using any model system, that advances our understanding of development, morphology, form and function, evolution, disease, stem cells, repair and regeneration.
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