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组织特异性、Gata6 驱动的转录程序指导成熟动脉树的重塑。

A tissue-specific, Gata6-driven transcriptional program instructs remodeling of the mature arterial tree.

机构信息

Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.

Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, United States.

出版信息

Elife. 2017 Sep 27;6:e31362. doi: 10.7554/eLife.31362.

DOI:10.7554/eLife.31362
PMID:28952437
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5630260/
Abstract

Connection of the heart to the systemic circulation is a critical developmental event that requires selective preservation of embryonic vessels (aortic arches). However, why some aortic arches regress while others are incorporated into the mature aortic tree remains unclear. By microdissection and deep sequencing in mouse, we find that neural crest (NC) only differentiates into vascular smooth muscle cells (SMCs) around those aortic arches destined for survival and reorganization, and identify the transcription factor Gata6 as a crucial regulator of this process. Gata6 is expressed in SMCs and its target genes activation control SMC differentiation. Furthermore, Gata6 is sufficient to promote SMCs differentiation in vivo, and drive preservation of aortic arches that ought to regress. These findings identify Gata6-directed differentiation of NC to SMCs as an essential mechanism that specifies the aortic tree, and provide a new framework for how mutations in GATA6 lead to congenital heart disorders in humans.

摘要

心脏与体循环的连接是一个关键的发育事件，需要选择性地保留胚胎血管（主动脉弓）。然而，为什么有些主动脉弓退化，而另一些则被纳入成熟的主动脉树，这仍然不清楚。通过在小鼠中的显微解剖和深度测序，我们发现神经嵴（NC）仅在那些注定要存活和重新组织的主动脉弓周围分化为血管平滑肌细胞（SMCs），并确定转录因子 Gata6 是这个过程的关键调节因子。Gata6 在 SMCs 中表达，其靶基因的激活控制 SMC 分化。此外，Gata6 足以在体内促进 SMCs 的分化，并促使本应退化的主动脉弓得以保留。这些发现确定了 Gata6 指导的 NC 向 SMCs 的分化是指定主动脉树的一个重要机制，并为 GATA6 中的突变如何导致人类先天性心脏疾病提供了一个新的框架。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d10/5630260/67817703337d/elife-31362-resp-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d10/5630260/cc32f1792f92/elife-31362-fig1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d10/5630260/35cfa10b279e/elife-31362-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d10/5630260/e2c19aa0ba7d/elife-31362-fig3-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d10/5630260/a2385f2e125a/elife-31362-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d10/5630260/aad8cb76e55b/elife-31362-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d10/5630260/bc2ed697a258/elife-31362-fig4-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d10/5630260/06588490d333/elife-31362-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d10/5630260/6d9c5f0db670/elife-31362-fig5-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d10/5630260/a0087245bea2/elife-31362-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d10/5630260/be3104e0fc91/elife-31362-resp-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d10/5630260/67817703337d/elife-31362-resp-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d10/5630260/cc32f1792f92/elife-31362-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d10/5630260/eeba05ff97d3/elife-31362-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d10/5630260/50193f2db394/elife-31362-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d10/5630260/35cfa10b279e/elife-31362-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d10/5630260/e2c19aa0ba7d/elife-31362-fig3-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d10/5630260/a2385f2e125a/elife-31362-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d10/5630260/aad8cb76e55b/elife-31362-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d10/5630260/bc2ed697a258/elife-31362-fig4-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d10/5630260/06588490d333/elife-31362-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d10/5630260/6d9c5f0db670/elife-31362-fig5-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d10/5630260/a0087245bea2/elife-31362-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d10/5630260/be3104e0fc91/elife-31362-resp-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d10/5630260/67817703337d/elife-31362-resp-fig2.jpg

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