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表达转胶蛋白的肌成纤维细胞通过TGFβ信号传导协调腹侧中线闭合。

Transgelin-expressing myofibroblasts orchestrate ventral midline closure through TGFβ signalling.

作者信息

Aldeiri Bashar, Roostalu Urmas, Albertini Alessandra, Wong Jason, Morabito Antonino, Cossu Giulio

机构信息

Manchester Academic Health Science Centre, Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK.

Royal Manchester Children's Hospital, Manchester M13 9WL, UK.

出版信息

Development. 2017 Sep 15;144(18):3336-3348. doi: 10.1242/dev.152843. Epub 2017 Aug 14.

DOI:10.1242/dev.152843
PMID:28807903
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5612253/
Abstract

Ventral body wall (VBW) defects are among the most common congenital malformations, yet their embryonic origin and underlying molecular mechanisms remain poorly characterised. Transforming growth factor beta (TGFβ) signalling is essential for VBW closure, but the responding cells are not known. Here, we identify in mouse a population of migratory myofibroblasts at the leading edge of the closing VBW that express the actin-binding protein transgelin (TAGLN) and TGFβ receptor (TGFβR). These cells respond to a temporally regulated TGFβ2 gradient originating from the epithelium of the primary body wall. Targeted elimination of TGFβR2 in TAGLN cells impairs midline closure and prevents the correct subsequent patterning of the musculature and skeletal components. Remarkably, deletion of in myogenic or chondrogenic progenitor cells does not manifest in midline defects. Our results indicate a pivotal significance of VBW myofibroblasts in orchestrating ventral midline closure by mediating the response to the TGFβ gradient. Altogether, our data enable us to distinguish highly regulated epithelial-mesenchymal signalling and successive cellular migration events in VBW closure that explain early morphological changes underlying the development of congenital VBW defects.

摘要

腹侧体壁（VBW）缺陷是最常见的先天性畸形之一，但其胚胎起源和潜在的分子机制仍不清楚。转化生长因子β（TGFβ）信号对于VBW闭合至关重要，但响应细胞尚不清楚。在这里，我们在小鼠中鉴定出一群迁移性肌成纤维细胞，它们位于闭合的VBW前缘，表达肌动蛋白结合蛋白反胶束蛋白（TAGLN）和TGFβ受体（TGFβR）。这些细胞对源自原始体壁上皮的受时间调控的TGFβ2梯度作出反应。在TAGLN细胞中靶向消除TGFβR2会损害中线闭合，并阻止肌肉组织和骨骼成分随后的正确模式形成。值得注意的是，在成肌或成软骨祖细胞中缺失不会表现为中线缺陷。我们的结果表明，VBW肌成纤维细胞在通过介导对TGFβ梯度的反应来协调腹侧中线闭合方面具有关键意义。总之，我们的数据使我们能够区分VBW闭合过程中高度调控的上皮-间充质信号传导和连续的细胞迁移事件，这些事件解释了先天性VBW缺陷发展背后的早期形态学变化。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/080b/5612253/b65332063378/develop-144-152843-g7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/080b/5612253/c1265b8fd717/develop-144-152843-g1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/080b/5612253/25ccc60f1b14/develop-144-152843-g2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/080b/5612253/f50005761ff3/develop-144-152843-g3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/080b/5612253/674395b44f73/develop-144-152843-g4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/080b/5612253/db5b676e2afe/develop-144-152843-g5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/080b/5612253/990075ed42aa/develop-144-152843-g6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/080b/5612253/b65332063378/develop-144-152843-g7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/080b/5612253/c1265b8fd717/develop-144-152843-g1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/080b/5612253/25ccc60f1b14/develop-144-152843-g2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/080b/5612253/f50005761ff3/develop-144-152843-g3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/080b/5612253/674395b44f73/develop-144-152843-g4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/080b/5612253/db5b676e2afe/develop-144-152843-g5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/080b/5612253/990075ed42aa/develop-144-152843-g6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/080b/5612253/b65332063378/develop-144-152843-g7.jpg

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