Atp7a determines a hierarchy of copper metabolism essential for notochord development

Bryce A. Mendelsohn, Chunyue Yin, Stephen L. Johnson, Thomas P. Wilm, Lilianna Solnica-Krezel, Jonathan D. Gitlin

Research output: Contribution to journalArticlepeer-review

107 Scopus citations


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.

Original languageEnglish
Pages (from-to)155-162
Number of pages8
JournalCell metabolism
Issue number2
StatePublished - Aug 2006




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