转录因子
Notch信号通路
生物
过氧化物酶体增殖物激活受体
心脏发育
细胞生物学
调节器
受体
内科学
胚胎干细胞
内分泌学
信号转导
基因
遗传学
医学
作者
Mayyasa Rammah,Magali Théveniau-Ruissy,Rachel Sturny,Francesca Rochais,Robert G. Kelly
出处
期刊:Circulation Research
[Ovid Technologies (Wolters Kluwer)]
日期:2022-10-28
卷期号:131 (10): 842-858
被引量:3
标识
DOI:10.1161/circresaha.122.320766
摘要
The arterial pole of the heart is a hotspot for life-threatening forms of congenital heart defects (CHDs). Development of this cardiac region occurs by addition of Second Heart Field (SHF) progenitor cells to the embryonic outflow tract (OFT) and subsequently the base of the ascending aorta and pulmonary trunk. Understanding the cellular and genetic mechanisms driving arterial pole morphogenesis is essential to provide further insights into the cause of CHDs.A synergistic combination of bioinformatic analysis and mouse genetics as well as embryo and explant culture experiments were used to dissect the cross-regulatory transcriptional circuitry operating in future subaortic and subpulmonary OFT myocardium.Here, we show that the lipid sensor PPARγ (peroxisome proliferator-activated receptor gamma) is expressed in future subpulmonary myocardium in the inferior wall of the OFT and that PPARγ signaling-related genes display regionalized OFT expression regulated by the transcription factor TBX1 (T-box transcription factor 1). Modulating PPARγ activity in ex vivo cultured embryos treated with a PPARγ agonist or antagonist or deleting Pparγ in cardiac progenitor cells using Mesp1-Cre reveals that Pparγ is required for addition of future subpulmonary myocardium and normal arterial pole development. Additionally, the non-canonical DLK1 (delta-like noncanonical Notch ligand 1)/NOTCH (Notch receptor 1)/HES1 (Hes family bHLH transcription factor 1) pathway negatively regulates Pparγ in future subaortic myocardium in the superior OFT wall.Together these results identify Pparγ as a regulator of regional transcriptional identity in the developing heart, providing new insights into gene interactions involved in congenital heart defects.
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