HAND transcription factors cooperatively specify the aorta and pulmonary trunk.
HAND transcription factors cooperatively specify the aorta and pulmonary trunk.
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手工转录因子合作指定主动脉和肺部躯干。
DOI：
10.1016/j.ydbio.2021.03.011
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发表时间：
2021-08
影响因子：
2.7
通讯作者：
Firulli AB
中科院分区：
文献类型：
--
作者：
Vincentz JW;Firulli BA;Toolan KP;Osterwalder M;Pennacchio LA;Firulli AB
先天性心脏病(CHDS)影响心脏流出道(OFT)，是导致发病率和死亡率的重要原因。OFT来源于迁移细胞群，包括心脏神经脊细胞(CNCCs)和次级心场(SHF)来源的心肌和心内膜。相关的转录因子HAND1和HAND2已被认为与人类先天性心脏病有关，涉及OFT。虽然Hand1在OFT中表达，但Hand1 NCC特异性条件性基因敲除小鼠(H1CKO)是可行的。在这里，我们显示这些H1CKO呈现低外显率的OFT表型，而SHF特异性的Hand1消融不显示任何心脏表型。此外，在cNCC中，HAND1和HAND2似乎在功能上是多余的，因为在NCC特定的H1CKO背景上HAND2的减少/消融会导致明显的OFT缺陷。双重条件的Hand1和Hand2 NCC基因敲除显示持续性动脉干(PTA)，外显率为100%。NCC谱系追踪和Sema3c原位mRNA表达表明，表达Sema3c的细胞定位错误，导致H1CKO；H2CKO胚胎OFT内存在畸形的隔桥。有趣的是，Hand1和Hand2在SHF内也有遗传上的相互作用，因为在杂合子Hand2背景上的SHF H1CKO表现出不完全外显的室间隔缺陷(VSD)。以前，我们发现了一种BMP、HAND2和GATA依赖的Hand1OFT增强子，足以在新生OFT和主动脉中驱动报告基因的表达。使用这些转录输入作为探针，我们发现了一个新的Hand2 OFT增强子，表明一种保守的BMP-GATA依赖机制在转录上调节这两个手因子。这些发现支持这一假说，即手因素解释cNCC内的BMP信号，以协同协调OFT的形态发生。
Congenital heart defects (CHDs) affecting the cardiac outflow tract (OFT) constitute a significant cause of morbidity and mortality. The OFT develops from migratory cell populations which include the cardiac neural crest cells (cNCCs) and secondary heart field (SHF) derived myocardium and endocardium. The related transcription factors HAND1 and HAND2 have been implicated in human CHDs involving the OFT. Although Hand1 is expressed within the OFT, Hand1 NCC-specific conditional knockout mice (H1CKOs) are viable. Here we show that these H1CKOs present a low penetrance of OFT phenotypes, whereas SHF-specific Hand1 ablation does not reveal any cardiac phenotypes. Further, HAND1 and HAND2 appear functionally redundant within the cNCCs, as a reduction/ablation of Hand2 on an NCC-specific H1CKO background causes pronounced OFT defects. Double conditional Hand1 and Hand2 NCC knockouts exhibit persistent truncus arteriosus (PTA) with 100% penetrance. NCC lineage-tracing and Sema3c in situ mRNA expression reveal that Sema3c-expressing cells are mis-localized, resulting in a malformed septal bridge within the OFTs of H1CKO;H2CKO embryos. Interestingly, Hand1 and Hand2 also genetically interact within the SHF, as SHF H1CKOs on a heterozygous Hand2 background exhibit Ventricular Septal Defects (VSDs) with incomplete penetrance. Previously, we identified a BMP, HAND2, and GATA-dependent Hand1 OFT enhancer sufficient to drive reporter gene expression within the nascent OFT and aorta. Using these transcription inputs as a probe, we identify a novel Hand2 OFT enhancer, suggesting that a conserved BMP-GATA dependent mechanism transcriptionally regulates both HAND factors. These findings support the hypothesis that HAND factors interpret BMP signaling within the cNCCs to cooperatively coordinate OFT morphogenesis.
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DOI：
10.1073/pnas.1016959108
发表时间：
2011-04-05
影响因子：
11.1
作者：
He, Aibin;Kong, Sek Won;Pu, William T.
通讯作者：
Pu, William T.
影响因子：
1.9
作者：
Borochowitz, Z;Shalev, SA;Tirosh, E
通讯作者：
Tirosh, E
影响因子：
10.8
作者：
Firulli, Beth A.;George, Rajani M.;Firulli, Anthony B.
通讯作者：
Firulli, Anthony B.
影响因子：
8.8
作者：
Laurent F;Girdziusaite A;Gamart J;Barozzi I;Osterwalder M;Akiyama JA;Lincoln J;Lopez-Rios J;Visel A;Zuniga A;Zeller R
通讯作者：
Zeller R
影响因子：
2.7
作者：
Barbosa, Ana C.;Funato, Noriko;Yanagisawa, Hiromi
通讯作者：
Yanagisawa, Hiromi