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Human Molecular Genetics Advance Access published online on January 6, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddi471
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© The Author 2006. Published by Oxford University Press. All rights reserved The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oupjournals.org
Received October 7, 2005
Revised December 31, 2005
Accepted December 31, 2005

Article

Transgenic Drosophila models of Noonan syndrome causing PTPN11 gain-of-function mutations

Kimihiko Oishi 1, Konstantin Gaengel 2, Srinivasan Krishnamoorthy 3, Kenichi Kamiya 1, In-Kyong Kim 1, Huiwen Ying 1, Ursula Weber 2, Lizabeth Perkins 3, Marco Tartaglia 4, Marek Mlodzik 2, Leslie Pick 5, and Bruce D. Gelb 6 *

1 Departments of Pediatrics and Human Genetics, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029 USA
2 Brookdale Department of Molecular, Cell and Developmental Biology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029 USA
3 Pediatric Surgical Research Lab, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
4 Laboratorio di Metabolismo e Biochimica Patologica, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome 00161, Italy
5 Department of Entomology, University of Maryland, 4112A Plant Sciences Building, College Park, MD 20742, USA
6 Departments of Pediatrics and Human Genetics, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1498, New York, NY 10029 USA

* To whom correspondence should be addressed.
Bruce D. Gelb, E-mail: bruce.gelb{at}mssm.edu


  Abstract

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 cswN308D'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.


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