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Distinct and Overlapping Functions of ptpn11 Genes in Zebrafish Development

The PTPN11 (protein-tyrosine phosphatase, non-receptor type 11) gene encodes SHP2, a cytoplasmic PTP that is essential for vertebrate development. Mutations in PTPN11 are associated with Noonan and LEOPARD syndrome. Human patients with these autosomal dominant disorders display various symptoms, inc...

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Autores principales: Bonetti, Monica, Rodriguez-Martinez, Virginia, Paardekooper Overman, Jeroen, Overvoorde, John, van Eekelen, Mark, Jopling, Chris, den Hertog, Jeroen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3988099/
https://www.ncbi.nlm.nih.gov/pubmed/24736444
http://dx.doi.org/10.1371/journal.pone.0094884
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author Bonetti, Monica
Rodriguez-Martinez, Virginia
Paardekooper Overman, Jeroen
Overvoorde, John
van Eekelen, Mark
Jopling, Chris
den Hertog, Jeroen
author_facet Bonetti, Monica
Rodriguez-Martinez, Virginia
Paardekooper Overman, Jeroen
Overvoorde, John
van Eekelen, Mark
Jopling, Chris
den Hertog, Jeroen
author_sort Bonetti, Monica
collection PubMed
description The PTPN11 (protein-tyrosine phosphatase, non-receptor type 11) gene encodes SHP2, a cytoplasmic PTP that is essential for vertebrate development. Mutations in PTPN11 are associated with Noonan and LEOPARD syndrome. Human patients with these autosomal dominant disorders display various symptoms, including short stature, craniofacial defects and heart abnormalities. We have used the zebrafish as a model to investigate the role of Shp2 in embryonic development. The zebrafish genome encodes two ptpn11 genes, ptpn11a and ptpn11b. Here, we report that ptpn11a is expressed constitutively and ptpn11b expression is strongly upregulated during development. In addition, the products of both ptpn11 genes, Shp2a and Shp2b, are functional. Target-selected inactivation of ptpn11a and ptpn11b revealed that double homozygous mutants are embryonic lethal at 5–6 days post fertilization (dpf). Ptpn11a-/-ptpn11b-/- embryos showed pleiotropic defects from 4 dpf onwards, including reduced body axis extension and craniofacial defects, which was accompanied by low levels of phosphorylated Erk at 5 dpf. Interestingly, defects in homozygous ptpn11a-/- mutants overlapped with defects in the double mutants albeit they were milder, whereas ptpn11b-/- single mutants did not show detectable developmental defects and were viable and fertile. Ptpn11a-/-ptpn11b-/- mutants were rescued by expression of exogenous ptpn11a and ptpn11b alike, indicating functional redundance of Shp2a and Shp2b. The ptpn11 mutants provide a good basis for further unravelling of the function of Shp2 in vertebrate development.
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spelling pubmed-39880992014-04-21 Distinct and Overlapping Functions of ptpn11 Genes in Zebrafish Development Bonetti, Monica Rodriguez-Martinez, Virginia Paardekooper Overman, Jeroen Overvoorde, John van Eekelen, Mark Jopling, Chris den Hertog, Jeroen PLoS One Research Article The PTPN11 (protein-tyrosine phosphatase, non-receptor type 11) gene encodes SHP2, a cytoplasmic PTP that is essential for vertebrate development. Mutations in PTPN11 are associated with Noonan and LEOPARD syndrome. Human patients with these autosomal dominant disorders display various symptoms, including short stature, craniofacial defects and heart abnormalities. We have used the zebrafish as a model to investigate the role of Shp2 in embryonic development. The zebrafish genome encodes two ptpn11 genes, ptpn11a and ptpn11b. Here, we report that ptpn11a is expressed constitutively and ptpn11b expression is strongly upregulated during development. In addition, the products of both ptpn11 genes, Shp2a and Shp2b, are functional. Target-selected inactivation of ptpn11a and ptpn11b revealed that double homozygous mutants are embryonic lethal at 5–6 days post fertilization (dpf). Ptpn11a-/-ptpn11b-/- embryos showed pleiotropic defects from 4 dpf onwards, including reduced body axis extension and craniofacial defects, which was accompanied by low levels of phosphorylated Erk at 5 dpf. Interestingly, defects in homozygous ptpn11a-/- mutants overlapped with defects in the double mutants albeit they were milder, whereas ptpn11b-/- single mutants did not show detectable developmental defects and were viable and fertile. Ptpn11a-/-ptpn11b-/- mutants were rescued by expression of exogenous ptpn11a and ptpn11b alike, indicating functional redundance of Shp2a and Shp2b. The ptpn11 mutants provide a good basis for further unravelling of the function of Shp2 in vertebrate development. Public Library of Science 2014-04-15 /pmc/articles/PMC3988099/ /pubmed/24736444 http://dx.doi.org/10.1371/journal.pone.0094884 Text en © 2014 Bonetti et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Bonetti, Monica
Rodriguez-Martinez, Virginia
Paardekooper Overman, Jeroen
Overvoorde, John
van Eekelen, Mark
Jopling, Chris
den Hertog, Jeroen
Distinct and Overlapping Functions of ptpn11 Genes in Zebrafish Development
title Distinct and Overlapping Functions of ptpn11 Genes in Zebrafish Development
title_full Distinct and Overlapping Functions of ptpn11 Genes in Zebrafish Development
title_fullStr Distinct and Overlapping Functions of ptpn11 Genes in Zebrafish Development
title_full_unstemmed Distinct and Overlapping Functions of ptpn11 Genes in Zebrafish Development
title_short Distinct and Overlapping Functions of ptpn11 Genes in Zebrafish Development
title_sort distinct and overlapping functions of ptpn11 genes in zebrafish development
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3988099/
https://www.ncbi.nlm.nih.gov/pubmed/24736444
http://dx.doi.org/10.1371/journal.pone.0094884
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