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

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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.
LanguageEnglish
Pages51-59
JournalMolecular Biosystems
Volume3
Issue number1
DOIs
StatusPublished - 2007

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Protein-Lysine 6-Oxidase
Notochord
Morphogenesis
Zebrafish
Metalloproteases
Oxides
Copper
Electron Microscopy
Collagen
Embryonic Structures

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Anderson, C., Bartlett, S. J., Gansner, J. M., Wilson, D., He, L., Gitlin, J. D., ... Dowden, J. (2007). Chemical genetics suggests a critical role for lysyl oxidase in zebrafiish notochord morphogenesis. DOI: 10.1039/b613673g

Chemical genetics suggests a critical role for lysyl oxidase in zebrafiish notochord morphogenesis. / Anderson, Carrie; Bartlett, Stephen J.; Gansner, John M.; Wilson, Duncan; He, Ling; Gitlin, Jonathan D.; Kelsh, Robert N.; Dowden, James.

In: Molecular Biosystems, Vol. 3, No. 1, 2007, p. 51-59.

Research output: Contribution to journalArticle

Anderson, C, Bartlett, SJ, Gansner, JM, Wilson, D, He, L, Gitlin, JD, Kelsh, RN & Dowden, J 2007, 'Chemical genetics suggests a critical role for lysyl oxidase in zebrafiish notochord morphogenesis' Molecular Biosystems, vol. 3, no. 1, pp. 51-59. DOI: 10.1039/b613673g
Anderson C, Bartlett SJ, Gansner JM, Wilson D, He L, Gitlin JD et al. Chemical genetics suggests a critical role for lysyl oxidase in zebrafiish notochord morphogenesis. Molecular Biosystems. 2007;3(1):51-59. Available from, DOI: 10.1039/b613673g
Anderson, Carrie ; Bartlett, Stephen J. ; Gansner, John M. ; Wilson, Duncan ; He, Ling ; Gitlin, Jonathan D. ; Kelsh, Robert N. ; Dowden, James. / Chemical genetics suggests a critical role for lysyl oxidase in zebrafiish notochord morphogenesis. In: Molecular Biosystems. 2007 ; Vol. 3, No. 1. pp. 51-59
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AB - 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.

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