Cardiovascular defects in a mouse model of HOXA1 syndrome
Cardiovascular defects in a mouse model of HOXA1 syndrome
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DOI：
10.1093/hmg/ddr434
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发表时间：
2012-01-01
影响因子：
3.5
通讯作者：
Capecchi, Mario R.
中科院分区：
文献类型：
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作者：
Makki, Nadja;Capecchi, Mario R.
先天性心脏病是人类最常见的出生缺陷之一，但许多调节心脏发育的基因和途径仍然未知。最近的一项人类研究显示，单个Hox基因HOXA 1（阿萨巴斯卡脑干发育不良综合征，Bosley-Salih-Alorainy综合征）的突变可导致严重的心血管畸形，其中一些在没有手术干预的情况下是致命的。自从人类综合征被发现以来，还没有任何Hox小鼠突变体具有心脏缺陷的报道，这阻碍了探索人类疾病发育原因的研究。在这项研究中，我们确定了严重的心血管畸形的Hox小鼠模型，模仿先天性心脏缺陷的HOXA 1综合征患者。Hoxa 1基因敲除小鼠表现出诸如主动脉弓中断、锁骨下动脉迷走和法洛四联症等缺陷，这表明Hoxa 1是大动脉和心脏流出道形成所必需的。我们发现，在早期胚胎发育过程中，Hoxa 1在心脏神经嵴细胞（NCC）的前体中表达，这些细胞分布在心脏中。我们进一步证明，Hoxa 1的行为上游的几个基因，重要的神经嵴规范。因此，我们的数据使我们能够提出一个模型，其中Hoxa 1通过影响心脏NCC来调节心脏发育，从而深入了解人类疾病的潜在机制。
Congenital heart disease is one of the most common human birth defects, yet many genes and pathways regulating heart development remain unknown. A recent study in humans revealed that mutations in a single Hox gene, HOXA1 (Athabascan Brainstem Dysgenesis Syndrome, Bosley-Salih-Alorainy Syndrome), can cause severe cardiovascular malformations, some of which are lethal without surgical intervention. Since the discovery of the human syndromes, there have been no reports of any Hox mouse mutants with cardiac defects, hampering studies to explore the developmental causes of the human disease. In this study, we identify severe cardiovascular malformations in a Hox mouse model, which mimic the congenital heart defects in HOXA1 syndrome patients. Hoxa1 null mice show defects such as interrupted aortic arch, aberrant subclavian artery and Tetralogy of Fallot, demonstrating that Hoxa1 is required for patterning of the great arteries and outflow tract of the heart. We show that during early embryogenesis, Hoxa1 is expressed in precursors of cardiac neural crest cells (NCCs), which populate the heart. We further demonstrate that Hoxa1 acts upstream of several genes, important for neural crest specification. Thus, our data allow us to suggest a model in which Hoxa1 regulates heart development through its influence on cardiac NCCs, providing insight into the mechanisms underlying the human disease.