A tissue-specific, Gata6-driven transcriptional program instructs remodeling of the mature arterial tree.
A tissue-specific, Gata6-driven transcriptional program instructs remodeling of the mature arterial tree.
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DOI：
10.7554/elife.31362
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发表时间：
2017-09-27
期刊：
影响因子：
7.7
通讯作者：
Bobola N
中科院分区：
文献类型：
--
作者：
Losa M;Latorre V;Andrabi M;Ladam F;Sagerström C;Novoa A;Zarrineh P;Bridoux L;Hanley NA;Mallo M;Bobola N
心脏与体循环的连接是一个关键的发育事件，需要选择性地保存胚胎血管（主动脉弓）。然而，为什么一些主动脉弓退化，而另一些被纳入成熟的主动脉树仍然不清楚。通过显微解剖和深度测序，我们发现神经嵴（NC）只分化为血管平滑肌细胞（SMC）周围的主动脉弓注定生存和重组，并确定转录因子Gata6作为这一过程的关键调节因子。Gata6在SMC中表达，其靶基因的激活控制SMC的分化。此外，Gata6足以促进SMC在体内分化，并驱动应该消退的主动脉弓的保存。这些发现将Gata6指导的NC向SMC分化确定为指定主动脉树的基本机制，并为GATA6突变如何导致人类先天性心脏病提供了新的框架。
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.