title: Distinct and overlapping functions of ptpn11 genes in Zebrafish development.
abstract: 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.
authors.affiliation: Hubrecht Institute-Koninklijke Nederlandse Akademie van Wetenschappen and University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Monica
authors.initials: M
authors.lastname: Bonetti
authors.affiliation: Hubrecht Institute-Koninklijke Nederlandse Akademie van Wetenschappen and University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Virginia
authors.initials: V
authors.lastname: Rodriguez-Martinez
authors.affiliation: Hubrecht Institute-Koninklijke Nederlandse Akademie van Wetenschappen and University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Paardekooper Overman
authors.affiliation: Hubrecht Institute-Koninklijke Nederlandse Akademie van Wetenschappen and University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: John
authors.initials: J
authors.lastname: Overvoorde
authors.affiliation: Hubrecht Institute-Koninklijke Nederlandse Akademie van Wetenschappen and University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: van Eekelen
authors.affiliation: Hubrecht Institute-Koninklijke Nederlandse Akademie van Wetenschappen and University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Chris
authors.initials: C
authors.lastname: Jopling
authors.affiliation: Hubrecht Institute-Koninklijke Nederlandse Akademie van Wetenschappen and University Medical Center Utrecht, Utrecht, The Netherlands; Institute of Biology, Leiden, Leiden, The Netherlands.
authors.forename: Jeroen den
authors.initials: Jd
authors.lastname: Hertog
mesh_terms: D000818:Animals; D001483:Base Sequence; D004625:Embryo, Nonmammalian / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D055786:Gene Knockout Techniques; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D009154:Mutation; D010641:Phenotype; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000172:deficiency / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics*; D029961:Zebrafish Proteins / Q000172:deficiency / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D029961:Zebrafish Proteins; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C000588865:protein tyrosine phosphatase, non-receptor type 11, a, zebrafish
references.citation: J Clin Invest. 2011 Mar;121(3):1026-43
references.pmid: 21339643
references.citation: Cell. 1995 Feb 10;80(3):473-83
references.pmid: 7859288
references.citation: Am J Hum Genet. 2002 Aug;71(2):389-94
references.pmid: 12058348
references.citation: Dev Dyn. 1995 Jul;203(3):253-310
references.pmid: 8589427
references.citation: Circulation. 2008 Mar 18;117(11):1423-35
references.pmid: 18316486
references.citation: Dev Cell. 2010 May 18;18(5):750-62
references.pmid: 20493809
references.citation: Rev Esp Cardiol (Engl Ed). 2013 Sep;66(9):756-7
references.pmid: 24773692
references.citation: Nat Med. 2004 Aug;10(8):849-57
references.pmid: 15273746
references.citation: Exp Cell Res. 1999 Nov 25;253(1):47-54
references.pmid: 10579910
references.citation: Science. 2006 Mar 3;311(5765):1287-90
references.pmid: 16439621
references.citation: Genome Res. 2003 Dec;13(12):2700-7
references.pmid: 14613981
references.citation: Development. 1993 Dec;119(4):1203-15
references.pmid: 8306883
references.citation: Cancer Cell. 2011 May 17;19(5):629-39
references.pmid: 21575863
references.citation: Mol Cell Biol. 2006 Jun;26(12):4664-74
references.pmid: 16738330
references.citation: Nat Rev Genet. 2007 May;8(5):353-67
references.pmid: 17440532
references.citation: Dis Model Mech. 2011 Mar;4(2):228-39
references.pmid: 21068439
references.citation: PLoS Genet. 2007 Dec;3(12):e225
references.pmid: 18159945
references.citation: Trends Biochem Sci. 2003 Jun;28(6):284-93
references.pmid: 12826400
references.citation: Dis Model Mech. 2013 Nov;6(6):1448-58
references.pmid: 24077964
references.citation: Hum Mol Genet. 2009 Jan 1;18(1):193-201
references.pmid: 18849586
references.citation: Am J Med Genet A. 2003 Nov 15;123A(1):68-71
references.pmid: 14556249
references.citation: Mol Cell Biol. 2010 May;30(10):2498-507
references.pmid: 20308328
references.citation: J Med Genet. 2002 Aug;39(8):571-4
references.pmid: 12161596
references.citation: FEBS Lett. 2006 May 1;580(10):2477-82
references.pmid: 16638574
references.citation: Am J Hum Genet. 2006 Feb;78(2):279-90
references.pmid: 16358218
references.citation: Nat Genet. 2001 Dec;29(4):465-8
references.pmid: 11704759
references.citation: J Biol Chem. 2013 Apr 12;288(15):10472-82
references.pmid: 23457302
references.citation: Am J Hum Genet. 2002 Jun;70(6):1555-63
references.pmid: 11992261
references.citation: Proc Natl Acad Sci U S A. 2009 Sep 8;106(36):15436-41
references.pmid: 19706403
references.citation: J Biol Chem. 1997 Aug 8;272(32):20038-43
references.pmid: 9242674
references.citation: Nature. 2004 Oct 21;431(7011):946-57
references.pmid: 15496914
references.citation: Dev Cell. 2006 Mar;10(3):317-27
references.pmid: 16516835
references.citation: Mol Syndromol. 2010 Feb;1(1):2-26
references.pmid: 20648242
references.citation: Cell Signal. 2008 Mar;20(3):453-9
references.pmid: 17993263
references.citation: Hum Mol Genet. 2006 Feb 15;15(4):543-53
references.pmid: 16399795
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: PLoS One. 2010 Sep 03;5(9):e12573
references.pmid: 20838449
references.citation: Mol Cell Biol. 2007 Oct;27(19):6706-17
references.pmid: 17646384
references.citation: J Biol Chem. 2006 Mar 10;281(10):6785-92
references.pmid: 16377799
references.citation: Proc Natl Acad Sci U S A. 2009 Jul 7;106(27):11270-5
references.pmid: 19541608
references.citation: Am J Dis Child. 1968 Oct;116(4):373-80
references.pmid: 4386970
references.citation: J Biol Chem. 2005 Sep 2;280(35):30984-93
references.pmid: 15987685
references.citation: Am J Dis Child. 1969 Jun;117(6):652-62
references.pmid: 5771505
references.citation: EMBO J. 1997 May 1;16(9):2352-64
references.pmid: 9171349
references.citation: Proc Natl Acad Sci U S A. 2004 Feb 10;101(6):1638-43
references.pmid: 14757817
references.citation: Proc Natl Acad Sci U S A. 2012 Mar 13;109(11):4257-62
references.pmid: 22371576