Abstract
Noonan syndrome is a common human autosomal dominant birth defect, characterized by short stature, facial abnormalities, heart defects and possibly increased risk of leukemia. Mutations of Ptpn11 (also known as Shp2), which encodes the protein-tyrosine phosphatase Shp2, occur in ∼50% of individuals with Noonan syndrome, but their molecular, cellular and developmental effects, and the relationship between Noonan syndrome and leukemia, are unclear. We generated mice expressing the Noonan syndrome–associated mutant D61G. When homozygous, the D61G mutant is embryonic lethal, whereas heterozygotes have decreased viability. Surviving Ptpn11D61G/+ embryos (∼50%) have short stature, craniofacial abnormalities similar to those in Noonan syndrome, and myeloproliferative disease. Severely affected Ptpn11D61G/+ embryos (∼50%) have multiple cardiac defects similar to those in mice lacking the Ras-GAP protein neurofibromin. Their endocardial cushions have increased Erk activation, but Erk hyperactivation is cell and pathway specific. Our results clarify the relationship between Noonan syndrome and leukemia and show that a single Ptpn11 gain-of-function mutation evokes all major features of Noonan syndrome by acting on multiple developmental lineages in a gene dosage–dependent and pathway-selective manner.
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References
Noonan, J.A. Hypertelorism with Turner phenotype. A new syndrome with associated congenital heart disease. Am. J. Dis. Child. 116, 373–380 (1968).
Nora, J.J., Nora, A.H., Sinha, A.K., Spangler, R.D. & Lubs, H.A. The Ullrich-Noonan syndrome (Turner phenotype). Am. J. Dis. Child. 127, 48–55 (1974).
Allanson, J.E. Noonan syndrome. J. Med. Genet. 24, 9–13 (1987).
Noonan, J.A. Noonan syndrome. An update and review for the primary pediatrician. Clin. Pediatr. (Phila.) 33, 548–555 (1994).
Marino, B., Digilio, M.C., Toscano, A., Giannotti, A. & Dallapiccola, B. Congenital heart diseases in children with Noonan syndrome: an expanded cardiac spectrum with high prevalence of atrioventricular canal. J. Pediatr. 135, 703–706 (1999).
Marino, B. et al. Noonan syndrome: structural abnormalities of the mitral valve causing subaortic obstruction. Eur. J. Pediatr. 154, 949–952 (1995).
Digilio, M.C. et al. Noonan syndrome and aortic coarctation. Am. J. Med. Genet. 80, 160–162 (1998).
Bertola, D.R. et al. Cardiac findings in 31 patients with Noonan's syndrome. Arq. Bras. Cardiol. 75, 409–412 (2000).
Bader-Meunier, B. et al. Occurrence of myeloproliferative disorder in patients with Noonan syndrome. J. Pediatr. 130, 885–889 (1997).
Johannes, J.M., Garcia, E.R., De Vaan, G.A. & Weening, R.S. Noonan's syndrome in association with acute leukemia. Pediatr. Hematol. Oncol. 12, 571–575 (1995).
Side, L.E. & Shannon, K.M. Myeloid disorders in infants with Noonan syndrome and a resident's “rule” recalled. J. Pediatr. 130, 857–859 (1997).
Tartaglia, M. et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat. Genet. 29, 465–468 (2001).
Kosaki, K. et al. PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) mutations in seven Japanese patients with Noonan syndrome. J. Clin. Endocrinol. Metab. 87, 3529–3533 (2002).
Maheshwari, M. et al. PTPN11 mutations in Noonan syndrome type I: detection of recurrent mutations in exons 3 and 13. Hum. Mutat. 20, 298–304 (2002).
Tartaglia, M. et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am. J. Hum. Genet. 70, 1555–1563 (2002).
Neel, B.G., Gu, H. & Pao, L. The 'Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends Biochem. Sci. 28, 284–293 (2003).
Araki, T., Nawa, H. & Neel, B.G. Tyrosyl phosphorylation of Shp2 is required for normal ERK activation in response to some, but not all, growth factors. J. Biol. Chem. 278, 41677–41684 (2003).
Barford, D. & Neel, B.G. Revealing mechanisms for SH2 domain mediated regulation of the protein tyrosine phosphatase SHP-2. Structure 6, 249–254 (1998).
Hof, P., Pluskey, S., Dhe-Paganon, S., Eck, M.J. & Shoelson, S.E. Crystal structure of the tyrosine phosphatase SHP-2. Cell 92, 441–450 (1998).
O'Reilly, A.M., Pluskey, S., Shoelson, S.E. & Neel, B.G. Activated mutants of SHP-2 preferentially induce elongation of Xenopus animal caps. Mol. Cell. Biol. 20, 299–311 (2000).
Tartaglia, M. et al. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat. Genet. 34, 148–150 (2003).
Loh, M.L. et al. Somatic mutations in PTPN11 implicate the protein tyrosine phosphatase SHP-2 in leukemogenesis. Blood 103, 2325–2331 (2003).
Tartaglia, M. et al. Genetic evidence for lineage- and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia. Blood 104, 307–313 (2004).
Musante, L. et al. Spectrum of mutations in PTPN11 and genotype-phenotype correlation in 96 patients with Noonan syndrome and five patients with cardio-facio-cutaneous syndrome. Eur. J. Hum. Genet. 11, 201–206 (2003).
Gitler, A.D. et al. Nf1 has an essential role in endothelial cells. Nat. Genet. 33, 75–79 (2003).
Ahmed, M.L. et al. Noonan's syndrome: abnormalities of the growth hormone/IGF-I axis and the response to treatment with human biosynthetic growth hormone. Acta Paediatr. Scand. 80, 446–450 (1991).
Jacks, T. et al. Tumour predisposition in mice heterozygous for a targeted mutation in Nf1. Nat. Genet. 7, 353–361 (1994).
Brannan, C.I. et al. Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues. Genes Dev. 8, 1019–1029 (1994).
Lakkis, M.M. & Epstein, J.A. Neurofibromin modulation of ras activity is required for normal endocardial-mesenchymal transformation in the developing heart. Development 125, 4359–4367 (1998).
Bahuau, M. et al. Exclusion of allelism of Noonan syndrome and neurofibromatosis-type 1 in a large family with Noonan syndrome-neurofibromatosis association. Am. J. Med. Genet. 66, 347–355 (1996).
Epstein, J.A. Developing models of DiGeorge syndrome. Trends Genet. 17, S13–S17 (2001).
Sarkozy, A. et al. Correlation between PTPN11 gene mutations and congenital heart defects in Noonan and LEOPARD syndromes. J. Med. Genet. 40, 704–708 (2003).
Braun, B.S. et al. Somatic activation of oncogenic Kras in hematopoietic cells initiates a rapidly fatal myeloproliferative disorder. Proc. Natl Acad. Sci. USA 101, 597–602 (2004).
Chan, I.T. et al. Conditional expression of oncogenic K-ras from its endogenous promoter induces a myeloproliferative disease. J. Clin. Invest. 113, 528–538 (2004).
Dieterlen-Lievre, F. Hematopoiesis: progenitors and their genetic program. Curr. Biol. 8, R727–R730 (1998).
Gitler, A.D. et al. Tie2-Cre-induced inactivation of a conditional mutant Nf1 allele in mouse results in a myeloproliferative disorder that models juvenile myelomonocytic leukemia. Pediatr. Res. 55, 581–584 (2004).
Couly, G.F., Coltey, P.M. & Le Douarin, N.M. The triple origin of skull in higher vertebrates: a study in quail-chick chimeras. Development 117, 409–429 (1993).
Kontges, G. & Lumsden, A. Rhombencephalic neural crest segmentation is preserved throughout craniofacial ontogeny. Development 122, 3229–3242 (1996).
Birchmeier, C., Birchmeier, W., Gherardi, E. & Vande Woude, G.F. Met, metastasis, motility and more. Nat. Rev. Mol. Cell Biol. 4, 915–925 (2003).
Ghosh, S. & Karin, M. Missing pieces in the NF-κB puzzle. Cell 109, S81–S96 (2002).
Kapoor, G.S., Zhan, Y., Johnson, G.R. & O'Rourke, D.M. Distinct domains in the SHP-2 phosphatase differentially regulate epidermal growth factor receptor/NF-κB activation through Gab1 in glioblastoma cells. Mol. Cell. Biol. 24, 823–836 (2004).
You, M., Flick, L.M., Yu, D. & Feng, G.S. Modulation of the nuclear factor kappa B pathway by Shp-2 tyrosine phosphatase in mediating the induction of interleukin (IL)-6 by IL-1 or tumor necrosis factor. J. Exp. Med. 193, 101–110 (2001).
Fragale, A., Tartaglia, M., Wu, J. & Gelb, B.D. Noonan syndrome–associated SHP2/PTPN11 mutants cause EGF-dependent prolonged GAB1 binding and sustained ERK2/MAPK1 activation. Hum. Mutat. 23, 267–277 (2004).
Tuveson, D.A. et al. Endogenous oncogenic K-rasG12D stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell 5, 375–387 (2004).
Itoh, M. et al. Role of Gab1 in heart, placenta, and skin development and growth factor- and cytokine-induced extracellular signal-regulated kinase mitogen-activated protein kinase activation. Mol. Cell. Biol. 20, 3695–3704 (2000).
Su, I.H. et al. Ezh2 controls B cell development through histone H3 methylation and Igh rearrangement. Nat. Immunol. 4, 124–131 (2003).
Zhang, S.Q. et al. Shp2 regulates SRC family kinase activity and Ras/Erk activation by controlling Csk recruitment. Mol. Cell 13, 341–355 (2004).
Klaman, L.D. et al. Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein-tyrosine phosphatase 1B-deficient mice. Mol. Cell. Biol. 20, 5479–5489 (2000).
Corson, L.B., Yamanaka, Y., Lai, K.M. & Rossant, J. Spatial and temporal patterns of ERK signaling during mouse embryogenesis. Development 130, 4527–4537 (2003).
Sattler, M. et al. Critical role for Gab2 in transformation by BCR/ABL. Cancer Cell 1, 479–492 (2002).
Acknowledgements
We thank C.J. Rosen and J. Burgess for measuring IGF-I levels in serum and W. Pu for helpful discussions. This work was supported by US National Institutes of Health (NIH) R01 CA49152 and DK66600 and a Translational Research Grant from the Leukemia and Lymphoma Society (to B.G.N.), NIH R01 HL62974 and HL61475 (to J.A.E.), N.I.H. P01 DK50654 (to B.G.N., D.G.G. and J.L.K.) and NIH R01 DK64730 (to I.R.W.). Flow cytometric studies were partially supported by Digestive Disease Research and Development Center grant NIH DK 64399. D.G.G. is an Investigator of the Howard Hughes Medical Institute. T. A. and M.G.M. were supported by fellowships from The Leukemia and Lymphoma Society. L.P. was supported by NIH training grant T32CA81156 and F.A.I. by NIH training grant T32HL007915.
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B.G.N. is a member of the Scientific Advisory Board and a Consultant for Ceptyr, Inc. However, the work described in this manuscript was not supported by Ceptyr or any other pharmaceutical company. The other authors have no potentially competing financial interests to declare.
Supplementary information
Supplementary Fig. 1
Comparison of mitral (MV) and tricuspid (TV) valves between E18.5 WT and Shp2D61G/+ embryos. (PDF 85 kb)
Supplementary Table 1
Progeny from Shp2D61G/+ matings. (PDF 114 kb)
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Araki, T., Mohi, M., Ismat, F. et al. Mouse model of Noonan syndrome reveals cell type– and gene dosage–dependent effects of Ptpn11 mutation. Nat Med 10, 849–857 (2004). https://doi.org/10.1038/nm1084
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DOI: https://doi.org/10.1038/nm1084
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