Distinct and overlapping functions of ptpn11 genes in Zebrafish development.
Distinct and overlapping functions of ptpn11 genes in Zebrafish development.
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DOI：
10.1371/journal.pone.0094884
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Hertog Jd
中科院分区：
文献类型：
--
作者：
Bonetti M;Rodriguez-Martinez V;Paardekooper Overman J;Overvoorde J;van Eekelen M;Jopling C;Hertog Jd
PTPN 11（蛋白酪氨酸磷酸酶，非受体11型）基因编码SHP 2，一种脊椎动物发育所必需的细胞质PTP。PTPN 11的突变与努南综合征和LEOPARD综合征有关。患有这些常染色体显性遗传疾病的人类患者表现出各种症状，包括身材矮小、颅面缺陷和心脏异常。我们已经使用斑马鱼作为模型来研究Shp 2在胚胎发育中的作用。斑马鱼基因组编码两个ptpn 11基因，ptpn 11 a和ptpn 11b。在这里，我们报告说，ptpn 11 a的组成性表达和ptpn 11b的表达强烈上调在发展过程中。此外，两个ptpn 11基因的产物Shp 2a和Shp 2b是功能性的。ptpn 11 a和ptpn 11b的靶向选择性失活显示，双纯合突变体在受精后5-6天（dpf）是胚胎致死的。Ptpn 11 a-/-ptpn 11b-/-胚胎从4 dpf开始表现出多效性缺陷，包括体轴延伸减少和颅面缺陷，5 dpf时伴有低水平的磷酸化Erk。有趣的是，纯合ptpn 11 a-/-突变体的缺陷与双突变体的缺陷重叠，尽管它们更温和，而ptpn 11b-/-单突变体没有显示出可检测的发育缺陷，并且是可行的和可育的。Ptpn 11 a-/-ptpn 11b-/-突变体通过外源ptpn 11 a和ptpn 11b的表达而被拯救，表明Shp 2a和Shp 2b的功能性减少。ptpn 11突变体为进一步阐明Shp 2在脊椎动物发育中的功能提供了良好的基础。
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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SHP2敲低和NOONAN/LEOPARD突变体SHP2诱导的胃部缺陷。
影响因子：
4.5
作者：
Jopling, Chris;van Geemen, Daphne;den Hertog, Jeroen
通讯作者：
den Hertog, Jeroen
影响因子：
15.9
作者：
Marin, Talita M.;Keith, Kimberly;Kontaridis, Maria I.
通讯作者：
Kontaridis, Maria I.
DOI：
10.1073/pnas.0903302106
发表时间：
2009-09-08
影响因子：
11.1
作者：
Nakamura, Tomoki;Gulick, James;Robbins, Jeffrey
通讯作者：
Robbins, Jeffrey
影响因子：
3.5
作者：
Hanna, Nadine;Montagner, Alexandra;Raynal, Patrick
通讯作者：
Raynal, Patrick
影响因子：
2.5
作者：
KIMMEL, CB;BALLARD, WW;SCHILLING, TF
通讯作者：
SCHILLING, TF