Chemical Genetics Suggests a Critical Role for Lysyl Oxidase in Zebrafish Notochord Morphogenesis

Overview

Journal Mol Biosyst

Publisher Royal Society of Chemistry

Specialties Biochemistry
Molecular Biology

Date 2007 Jan 12

PMID 17216056

Citations 21

Authors

Carrie Anderson

Stephen J Bartlett

John M Gansner

Duncan Wilson

Ling He

Jonathan D Gitlin

Robert N Kelsh

James Dowden

Affiliations

Soon will be listed here.

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-mercaptopyridine-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.

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