Transgenic Drosophila models of Noonan syndrome causing PTPN11 gain-of-function mutations
Transgenic Drosophila models of Noonan syndrome causing PTPN11 gain-of-function mutations
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DOI：
10.1093/hmg/ddi471
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发表时间：
2006-02-15
影响因子：
3.5
通讯作者：
Gelb, BD
中科院分区：
文献类型：
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作者：
Oishi, K;Gaengel, K;Gelb, BD
编码蛋白酪氨酸磷酸酶SHP-2的PTPN11基因突变导致努南综合征（NS），这是一种常染色体显性遗传病，伴有多型发育异常。某些种系和体细胞PTPN11突变导致白血病。突变具有功能获得（GOF）效应，最常见的NS等位基因N308D比引起白血病的突变弱。为了研究疾病相关的PTPN11等位基因的作用，我们用gal4诱导的转基因果蝇表达了PTPN11的野生型或突变型csw。所有三个转基因突变体csw都挽救了一个半形csw等位基因的眼睛表型，记录了活性。两种强csw突变等位基因的普遍表达是致命的，但不会干扰某些csw依赖性受体酪氨酸激酶途径的发育。普遍表达较弱的N308D等位基因引起翼静脉异位，与EGFR GOF表型相同。结果表明，csw（N308D）的异位翼静脉表型需要完整的EGF配体和受体，并且该转基因基因与Notch、DPP和JAK/STAT信号相互作用。突变体csw转基因的表达增加了RAS-MAP激酶的激活，这对于转导其表型是必要的，但不是充分的。这些苍蝇模型的发现提供了在哺乳动物模型中可测试的假设，在哺乳动物模型中，这些信号盒在很大程度上是保守的。此外，这些果蝇模型可用于敏化筛选，以鉴定新的相互作用基因，以及用于高通量筛选NS和ptpn11相关癌症的治疗化合物。
Mutations in the PTPN11 gene, which encodes the protein tyrosine phosphatase SHP-2, causes Noonan syndrome (NS), an autosomal dominant disorder with pleomorphic developmental abnormalities. Certain germline and somatic PTPN11 mutations cause leukemias. Mutations have gain-of-function (GOF) effects with the commonest NS allele, N308D, being weaker than the leukemia-causing mutations. To study the effects of disease-associated PTPN11 alleles, we generated transgenic fruitflies with GAL4-inducible expression of wild-type or mutant csw, the Drosophila orthologue of PTPN11. All three transgenic mutant CSWs rescued a hypomorphic csw allele's eye phenotype, documenting activity. Ubiquitous expression of two strong csw mutant alleles were lethal, but did not perturb development from some CSW-dependent receptor tyrosine kinase pathways. Ubiquitous expression of the weaker N308D allele caused ectopic wing veins, identical to the EGFR GOF phenotype. Epistatic analyses established that csw(N308D)'s ectopic wing vein phenotype required intact EGF ligand and receptor, and that this transgene interacted genetically with Notch, DPP and JAK/STAT signaling. Expression of the mutant csw transgenes increased RAS-MAP kinase activation, which was necessary but not sufficient for transducing their phenotypes. The findings from these fly models provided hypotheses testable in mammalian models, in which these signaling cassettes are largely conserved. In addition, these fly models can be used for sensitized screens to identify novel interacting genes as well as for high-throughput screening of therapeutic compounds for NS and PTPN11-related cancers.