Abstract
The tyrosine phosphatase Shp2 is recruited into tyrosine-kinase signalling pathways through binding of its two amino-terminal SH2 domains to specific phosphotyrosine motifs, concurrent with its re-localization and stimulation of phosphatase activity1. Shp2 can potentiate signalling through the MAP-kinase pathway2,3,4,5,6 and is required during early mouse development for gastrulation4,7. Chimaeric analysis can identify, by study of phenotypically normal embryos, tissues that tolerate mutant cells (and therefore do not require the mutated gene) or lack mutant cells (and presumably require the mutated gene during their developmental history8). We therefore generated chimaeric mouse embryos to explore the cellular requirements for Shp2. This analysis revealed an obligatory role for Shp2 during outgrowth of the limb. Shp2 is specifically required in mesenchyme cells of the progress zone (PZ), directly beneath the distal ectoderm of the limb bud. Comparison of Ptpn11 (encoding Shp2)-mutant and Fgfr1 (encoding fibroblast growth factor receptor-1)-mutant chimaeric limbs indicated that in both cases mutant cells fail to contribute to the PZ of phenotypically normal chimaeras, leading to the hypothesis that a signal transduction pathway, initiated by Fgfr1 and acting through Shp2, is essential within PZ cells. Rather than integrating proliferative signals, Shp2 probably exerts its effects on limb development by influencing cell shape, movement or adhesion. Furthermore, the branchial arches, which also use Fgfs during bud outgrowth, similarly require Shp2. Thus, Shp2 regulates phosphotyrosine-signalling events during the complex ectodermal-mesenchymal interactions that regulate mammalian budding morphogenesis.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Hof, P., Pluskey, S., Dhe, P.S., Eck, M.J. & Shoelson, S.E. Crystal structure of the tyrosine phosphatase SHP-2. Cell 92, 441–450 (1998).
Tang, T.L., Freeman, R.J., O'Reilly, A.M., Neel, B.G. & Sokol, S.Y. The SH2-containing protein-tyrosine phosphatase SH-PTP2 is required upstream of MAP kinase for early Xenopus development. Cell 80, 473–483 (1995).
Bennett, A.M., Hausdorff, S.F., O'Reilly, A.M., Freeman, R.M. & Neel, B.G. Multiple requirements for SHPTP2 in epidermal growth factor-mediated cell cycle progression. Mol. Cell. Biol. 16, 1189–1202 (1996).
Saxton, T.M. et al. Abnormal mesoderm patterning in mouse embryos mutant for the SH2 tyrosine phosphatase Shp-2. EMBO J. 16, 2352–2364 (1997).
O'Reilly, A.M. & Neel, B.G. Structural determinants of SHP-2 function and specificity in Xenopus mesoderm induction. Mol. Cell. Biol. 18, 161–177 (1998).
Oh, E.S. et al. Regulation of early events in integrin signaling by protein tyrosine phosphatase SHP-2. Mol. Cell. Biol. 19, 3205–3215 (1999).
Saxton, T.M. & Pawson, T. Morphogenetic movements at gastrulation require the SH2 tyrosine phosphatase Shp2. Proc. Natl Acad. Sci. USA 96, 3790–3795 (1999).
Rossant, J. & Spence, A. Chimeras and mosaics in mouse mutant analysis. Trends Genet. 14, 358–363 (1998).
Wood, S.A., Allen, N.D., Rossant, J., Auerbach, A. & Nagy, A. Non-injection methods for the production of embryonic stem cell-embryo chimaeras. Nature 365, 87–89 (1993).
Ciruna, B.G., Schwartz, L., Harpal, K., Yamaguchi, T.P. & Rossant, J. Chimeric analysis of fibroblast growth factor receptor-1 (Fgfr1) function: a role for FGFR1 in morphogenetic movement through the primitive streak. Development 124, 2829–2841 (1997).
Deng, C. et al. Fibroblast growth factor receptor-1 (FGFR-1) is essential for normal neural tube and limb development. Dev. Biol. 185, 42–54 (1997).
Gardner, R.L. & Cockroft, D.L. Complete dissipation of coherent clonal growth occurs before gastrulation in mouse epiblast. Development 125, 2397–2402 (1998).
Johnson, R.L. & Tabin, C.J. Molecular models for vertebrate limb development. Cell 90, 979–990 (1997).
Martin, G.R. The roles of FGFs in the early development of vertebrate limbs. Genes Dev. 12, 1571–1586 (1998).
Crossley, P.H. & Martin, G.R. The mouse Fgf8 gene encodes a family of polypeptides and is expressed in regions that direct outgrowth and patterning in the developing embryo. Development 121, 439–451 (1995).
Xu, X. et al. Fibroblast growth factor receptor 2 (FGFR2)-mediated reciprocal regulation loop between FGF8 and FGF10 is essential for limb induction. Development 125, 753–765 (1998).
Manes, S. et al. Concerted activity of tyrosine phosphatase SHP-2 and focal adhesion kinase in regulation of cell motility. Mol. Cell. Biol. 19, 3125–3135 (1999).
Fujioka, Y. et al. A novel membrane glycoprotein, SHPS-1, that binds the SH2-domain-containing protein tyrosine phosphatase SHP-2 in response to mitogens and cell adhesion. Mol. Cell. Biol. 16, 6887–6899 (1996).
Jackson, D.E., Ward, C.M., Wang, R. & Newman, P.J. The protein-tyrosine phosphatase SHP-2 binds platelet/endothelial cell adhesion molecule-1 (PECAM-1) and forms a distinct signaling complex during platelet aggregation. Evidence for a mechanistic link between PECAM-1- and integrin-mediated cellular signaling. J. Biol. Chem. 272, 6986–6993 (1997).
Li, S. & Muneoka, K. Cell migration and chick limb development: chemotactic action of FGF-4 and the AER. Dev. Biol. 211, 335–347 (1999).
Ede, D.A. & Law, J.T. Computer simulation of vertebrate limb morphogenesis. Nature 221, 244–248 (1969).
Bowen, J., Hinchliffe, J.R., Horder, T.J. & Reeve, A.M. The fate map of the chick forelimb-bud and its bearing on hypothesized developmental control mechanisms. Anat. Embryol. (Berl.) 179, 269–283 (1989).
Yu, D.H., Qu, C.K., Henegariu, O., Lu, X. & Feng, G.S. Protein-tyrosine phosphatase Shp-2 regulates cell spreading, migration, and focal adhesion. J. Biol. Chem. 273, 21125–21131 (1998).
Riddle, R.D. et al. Induction of the LIM homeobox gene Lmx1 by WNT7a establishes dorsoventral pattern in the vertebrate limb. Cell 83, 631–640 (1995).
Vogel, A., Roberts, C.D. & Niswander, L. Effect of FGF on gene expression in chick limb bud cells in vivo and in vitro. Dev. Biol. 171, 507–520 (1995).
Hogan, B.L. Morphogenesis. Cell 96, 225–233 (1999).
Neel, B.G. & Tonks, N.K. Protein tyrosine phosphatases in signal transduction. Curr. Opin. Cell. Biol. 9, 193–204 (1997).
Conlon, R.A. & Rossant, J. Exogenous retinoic acid rapidly induces anterior ectopic expression of murine Hox-2 genes in vivo. Development 116, 357–368 (1992).
Gertler, F.B., Niebuhr, K., Reinhard, M., Wehland, J. & Soriano, P. Mena, a relative of VASP and Drosophila Enabled, is implicated in the control of microfilament dynamics. Cell 87, 227–239 (1996).
Kimura, Y. et al. Cadherin-11 expressed in association with mesenchymal morphogenesis in the head, somite, and limb bud of early mouse embryos. Dev. Biol. 169, 347–358 (1995).
Acknowledgements
We thank A. Cheng for BrdU injections; S. McMaster for animal husbandry; D. Duboule and R. Johnson for Hoxd13 and Lmx1b in situ probes, respectively; F. Gertler for the anti-Mena antibody; and G.R. Martin for critically reading the manuscript. Predoctoral support for T.M.S. was from the Medical Research Council of Canada. This work was supported by a grant from Bristol Myers-Squibb, a Terry Fox Programme grant from the National Cancer Institute of Canada and a Howard Hughes International Scholar award to T.P.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Saxton, T., Ciruna, B., Holmyard, D. et al. The SH2 tyrosine phosphatase Shp2 is required for mammalian limb development. Nat Genet 24, 420–423 (2000). https://doi.org/10.1038/74279
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/74279
This article is cited by
-
RNA-Seq Analysis Reveals Altered Expression of Cell Adhesion-Related Genes Following PZR Knockout in Lung Cancer Cells
Applied Biochemistry and Biotechnology (2023)
-
Protein tyrosine phosphatases in skeletal development and diseases
Bone Research (2022)
-
A comprehensive review of SHP2 and its role in cancer
Cellular Oncology (2022)
-
From Stem to Sternum: The Role of Shp2 in the Skeleton
Calcified Tissue International (2022)
-
Modulation of α-catenin Tyr phosphorylation by SHP2 positively effects cell transformation induced by the constitutively active FGFR3
Oncogene (2006)