Conotruncal malformations are a major cause of congenital heart defects in newborn infants. Recently, genetic screens in humans and in mouse models have identified mutations in LRP2, a multi-ligand receptor, as a novel cause of a common arterial trunk, a severe form of outflow tract (OFT) defect. Yet, the underlying mechanism why the morphogen receptor LRP2 is essential for OFT development remained unexplained. Studying LRP2-deficient mouse models, we now show that LRP2 is expressed in the cardiac progenitor niche of the anterior second heart field (SHF) that contributes to elongation of the OFT during separation into aorta and pulmonary trunk. Loss of LRP2 in mutant mice results in depletion of a pool of sonic hedgehog-dependent progenitor cells in the anterior SHF due to premature differentiation into cardiomyocytes as they migrate into the OFT myocardium. Depletion of this cardiac progenitor cell pool results in aberrant shortening of the OFT, the likely cause of CAT formation in affected mice. Our findings identified the molecular mechanism whereby LRP2 controls maintenance of progenitor cell fate in the anterior SHF essential for OFT separation, and why receptor dysfunction is a novel cause of conotruncal malformation.

中文翻译：

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LRP2 在流出道形成过程中控制心脏祖细胞的声波刺猬依赖性分化。


圆锥干畸形是新生儿先天性心脏缺陷的主要原因。最近，人类和小鼠模型的基因筛查发现LRP2（一种多配体受体）的突变是导致总动脉干（一种严重的流出道 (OFT) 缺陷）的新原因。然而，形态发生素受体 LRP2 对于 OFT 发育至关重要的潜在机制仍不清楚。通过研究 LRP2 缺陷小鼠模型，我们现在发现 LRP2 在前第二心区 (SHF) 的心脏祖细胞微环境中表达，在分离为主动脉和肺干期间有助于 OFT 伸长。突变小鼠中 LRP2 的缺失会导致前部 SHF 中一群声波刺猬依赖性祖细胞的耗尽，因为它们在迁移到 OFT 心肌时过早分化为心肌细胞。心脏祖细胞库的耗尽会导致 OFT 异常缩短，这可能是受影响小鼠中 CAT 形成的原因。我们的研究结果确定了 LRP2 控制前部 SHF 祖细胞命运维持的分子机制，这对于 OFT 分离至关重要，以及为什么受体功能障碍是圆锥干畸形的新原因。