Atp7a determines a hierarchy of copper metabolism essential for notochord development
Atp7a determines a hierarchy of copper metabolism essential for notochord development
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DOI：
10.1016/j.cmet.2006.05.001
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发表时间：
2006-08-01
期刊：
影响因子：
29
通讯作者：
Gitlin, Jonathan D.
中科院分区：
文献类型：
--
作者：
Mendelsohn, Bryce A.;Yin, Chunyue;Gitlin, Jonathan D.
胚胎发生过程中铜代谢的关键发育和遗传需求尚不清楚。利用斑马鱼的化学遗传筛选，我们确定了扰乱铜稳态的小分子。我们的研究结果揭示了铜在脊索形成中的作用，并证明了胚胎内铜代谢的层次结构。为了阐明这些观察结果，我们对铜缺乏表型的胚胎进行了遗传筛选，发现了Menkes病基因（atp7a）在斑马鱼同源物中的突变缺陷。人体ATP7A可恢复灾难中的铜代谢，移植实验显示ATP7A可自主发挥细胞功能，这一发现具有重要的治疗意义。atp7a基因的剂量决定了铜剥夺的敏感性，揭示了观察到的铜代谢的发育层次是由特定的遗传因素决定的。我们的数据为铜代谢的发育病理生理学提供了见解，并提示铜代谢不理想可能导致出生缺陷。
The critical developmental and genetic requirements of copper metabolism during embryogenesis are unknown. Utilizing a chemical genetic screen in zebrafish, we identified small molecules that perturb copper homeostasis. Our findings reveal a role for copper in notochord formation and demonstrate a hierarchy of copper metabolism within the embryo. To elucidate these observations, we interrogated a genetic screen for embryos phenocopied by copper deficiency, identifying calamity, a mutant defective in the zebrafish ortholog of the Menkes disease gene (atp7a). Copper metabolism in calamity is restored by human ATP7A, and transplantation experiments reveal that atp7a functions cell autonomously, findings with important therapeutic implications. The gene dosage of atp7a determines the sensitivity to copper deprivation, revealing that the observed developmental hierarchy of copper metabolism is informed by specific genetic factors. Our data provide insight into the developmental pathophysiology of copper metabolism and suggest that suboptimal copper metabolism may contribute to birth defects.