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The small molecule Mek1/2 inhibitor U0126 disrupts the chordamesoderm to notochord transition in zebrafish

Hawkins, TA; Cavodeassi, F; Erdelyi, F; Szabo, G; Lele, Z; (2008) The small molecule Mek1/2 inhibitor U0126 disrupts the chordamesoderm to notochord transition in zebrafish. BMC Developmental Biology , 8 , Article 42. 10.1186/1471-213X-8-42. Green open access

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Abstract

Background: Key molecules involved in notochord differentiation and function have been identified through genetic analysis in zebrafish and mice, but MEK1 and 2 have so far not been implicated in this process due to early lethality (Mek1(-/-)) and functional redundancy (Mek2(-/-)) in the knockout animals.Results: Here, we reveal a potential role for Mek1/2 during notochord development by using the small molecule Mek1/2 inhibitor U0126 which blocks phosphorylation of the Mek1/2 target gene Erk1/2 in vivo. Applying the inhibitor from early gastrulation until the 18-somite stage produces a specific and consistent phenotype with lack of dark pigmentation, shorter tail and an abnormal, undulated notochord. Using morphological analysis, in situ hybridization, immunhistochemistry, TUNEL staining and electron microscopy, we demonstrate that in treated embryos the chordamesoderm to notochord transition is disrupted and identify disorganization in the medial layer of the perinotochordal basement mebrane as the probable cause of the undulations and bulges in the notochord. We also examined and excluded FGF as the upstream signal during this process.Conclusion: Using the small chemical U0126, we have established a novel link between MAPK-signaling and notochord differentiation. Our phenotypic analysis suggests a potential connection between the MAPK-pathway, the COPI-mediated intracellular transport and/or the copper-dependent posttranslational regulatory processes during notochord differentiation.

Type: Article
Title: The small molecule Mek1/2 inhibitor U0126 disrupts the chordamesoderm to notochord transition in zebrafish
Open access status: An open access version is available from UCL Discovery
DOI: 10.1186/1471-213X-8-42
Publisher version: http://dx.doi.org/10.1186/1471-213X-8-42
Language: English
Additional information: © 2008 Hawkins et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: MUTATIONS AFFECTING DEVELOPMENT, DORSOVENTRAL PATTERN-FORMATION, ACTIVATED PROTEIN-KINASES, FIBROBLAST-GROWTH-FACTOR, LYSYL OXIDASE, SIGNALING PATHWAYS, GENE-EXPRESSION, NO TAIL, PHOSPHATIDYLINOSITOL-3 KINASE, CONVERGENT EXTENSION
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
URI: https://discovery.ucl.ac.uk/id/eprint/179354
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