Chemical genetics suggests a critical role for lysyl oxidase in zebrafiish notochord morphogenesis

Carrie Anderson, Stephen J. Bartlett, John M. Gansner, Duncan Wilson, Ling He, Jonathan D. Gitlin, Robert N. Kelsh, James Dowden

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

As a result of a chemical genetic screen for modulators of metalloprotease activity, we report that 2-mercaptopyridine-N-oxide induces a conspicuous undulating notochord defect in zebrafish embryos, a phenocopy of the leviathan mutant. The location of the chemically-induced wavy notochord correlated with the timing of application, thus defining a narrow chemical sensitivity window during segmentation stages. Microscopic observations revealed that notochord undulations appeared during the phase of notochord cell vacuolation and notochord elongation. Notochord cells become swollen as well as disorganized, while electron microscopy revealed disrupted organization of collagen fibrils in the surrounding sheath. We demonstrate by assay in zebrafish extracts that 2-mercaptopyidine-N-oxide inhibits lysyl oxidase. Thus, we provide insight into notochord morphogenesis and reveal novel compounds for lysyl oxidase inhibition. Taken together, these data underline the utility of small molecules for elucidating the dynamic mechanisms of early morphogenesis and provide a potential explanation for the recently established role of copper in zebrafish notochord formation.
Original languageEnglish
Pages (from-to)51-59
JournalMolecular Biosystems
Volume3
Issue number1
DOIs
Publication statusPublished - 2007

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