Id genes are essential for early heart formation.
Id genes are essential for early heart formation.
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DOI：
10.1101/gad.300400.117
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发表时间：
2017-07-01
影响因子：
10.5
通讯作者：
Colas AR
中科院分区：
文献类型：
--
作者：
Cunningham TJ;Yu MS;McKeithan WL;Spiering S;Carrette F;Huang CT;Bushway PJ;Tierney M;Albini S;Giacca M;Mano M;Puri PL;Sacco A;Ruiz-Lozano P;Riou JF;Umbhauer M;Duester G;Mercola M;Colas AR
坎宁安等人。证明螺旋-环-螺旋蛋白的 Id 家族对于指导从青蛙胚胎到人类胚胎干细胞的心源性中胚层的形成是必要且充分的。破译控制心脏规格的基本机制对于我们了解胚胎发育过程中心脏形成的启动以及将干细胞生物学应用于再生医学和疾病建模至关重要。使用系统且公正的功能筛选方法，我们发现螺旋-环-螺旋蛋白的 Id 家族对于指导青蛙胚胎和人类胚胎干细胞中心脏中胚层的形成既必要又充分。从机制上讲，Id 蛋白通过抑制心源性中胚层形成的两种抑制剂（Tcf3 和 Foxa2）并激活诱导剂 Evx1、Grrp1 和 Mesp1 来指定心肌细胞的命运。最重要的是，CRISPR/Cas9 介导的小鼠胚胎中整个 Id (Id1-4) 家族的消融导致前心脏祖细胞规范失败和无心胚胎的发育。因此，Id蛋白在心脏形成过程中发挥着核心且进化上保守的作用，并为再生医学和药物发现应用提供了有效产生心血管祖细胞的新方法。
Cunningham et al. demonstrate that the Id family of helix–loop–helix proteins is both necessary and sufficient to direct cardiogenic mesoderm formation from frog embryos to human embryonic stem cells. Deciphering the fundamental mechanisms controlling cardiac specification is critical for our understanding of how heart formation is initiated during embryonic development and for applying stem cell biology to regenerative medicine and disease modeling. Using systematic and unbiased functional screening approaches, we discovered that the Id family of helix–loop–helix proteins is both necessary and sufficient to direct cardiac mesoderm formation in frog embryos and human embryonic stem cells. Mechanistically, Id proteins specify cardiac cell fate by repressing two inhibitors of cardiogenic mesoderm formation—Tcf3 and Foxa2—and activating inducers Evx1, Grrp1, and Mesp1. Most importantly, CRISPR/Cas9-mediated ablation of the entire Id (Id1–4) family in mouse embryos leads to failure of anterior cardiac progenitor specification and the development of heartless embryos. Thus, Id proteins play a central and evolutionarily conserved role during heart formation and provide a novel means to efficiently produce cardiovascular progenitors for regenerative medicine and drug discovery applications.
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