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Molecular and Cellular Biology, July 2003, p. 4586-4597, Vol. 23, No. 13
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.13.4586-4597.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

The Murine Nck SH2/SH3 Adaptors Are Important for the Development of Mesoderm-Derived Embryonic Structures and for Regulating the Cellular Actin Network

Friedhelm Bladt,1,2 Elke Aippersbach,1,2 Sigal Gelkop,1,2 Geraldine A. Strasser,3 Piers Nash,1,2 Anna Tafuri,4,5,6,7 Frank B. Gertler,3 and Tony Pawson1,2*

Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5,1 Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario M5S 1A8,2 Advanced Medical Discovery Institute,4 Ontario Cancer Institute,5 Departments of Medical Biophysics,6 Immunology, University of Toronto, Toronto, Ontario M5G 2C1, Canada,7 Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts3

Received 25 November 2002/ Returned for modification 14 January 2003/ Accepted 24 March 2003

Mammalian Nck1 and Nck2 are closely related adaptor proteins that possess three SH3 domains, followed by an SH2 domain, and are implicated in coupling phosphotyrosine signals to polypeptides that regulate the actin cytoskeleton. However, the in vivo functions of Nck1 and Nck2 have not been defined. We have mutated the murine Nck1 and Nck2 genes and incorporated ß-galactosidase reporters into the mutant loci. In mouse embryos, the two Nck genes have broad and overlapping expression patterns. They are functionally redundant in the sense that mice deficient for either Nck1 or Nck2 are viable, whereas inactivation of both Nck1 and Nck2 results in profound defects in mesoderm-derived notochord and embryonic lethality at embryonic day 9.5. Fibroblast cell lines derived from Nck1-/- Nck2-/- embryos have defects in cell motility and in the organization of the lamellipodial actin network. These data suggest that the Nck SH2/SH3 adaptors have important functions in the development of mesodermal structures during embryogenesis, potentially linked to a role in cell movement and cytoskeletal organization.

* Corresponding author. Mailing address: Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Ave., Toronto, Ontario M5G 1X5, Canada. Phone: (416) 586-8262. Fax: (416) 586-8869. E-mail: pawson{at}mshri.on.ca.

Molecular and Cellular Biology, July 2003, p. 4586-4597, Vol. 23, No. 13
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.13.4586-4597.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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