International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


POSTER 117 - DISRUPTION OF THE IMPRINTED GENE GRB10 IN MICE LEADS TO DISPROPORTIONATE OVERGROWTH WITH EFFECTS ON METABOLISM

Smith F M
University of Bath, Centre for Regenerative Medicine, Department of Biology and Biochemistry

Co-Authors: 1) Charalambous M, 2) Bennett W R, 1) Crew T E, 3)Mackenzie F, 1) Ward A.
Institutions: 1) University of Bath, Centre for Regenerative Medicine, Department of Biology and Biochemistry. 2) University of Manchester, UK Centre for Tissue Engineering. 3) Medical Research Council, Mammalian Genetics Unit, Harwell, UK.

Growth Factor Receptor-bound protein 10 (Grb10) is a member of the Grb7 family of SH2 domain-containing adaptor proteins. Murine Grb10 is a maternally expressed gene located on proximal chromosome 11 and mice with uniparental disomy (UPD) of this region exhibit reciprocal growth phenotypes with pUPD resulting in overgrowth and mUPD in growth retardation. The equivalent human chromosomal region (7p11.2-p13) is associated with Silver-Russell Syndrome (SRS), which is characterised by pre- and post-natal growth restriction with mUPD7 occurring in 7% of cases. Grb10 is therefore a candidate gene responsible for the imprinted growth effects of UPD11 in mice and for SRS in humans. In vitro interactions of Grb10 with a number of activated tyrosine kinase receptors including Insr and Igf1r have been documented, although its function and signalling remain unclear. We have generated mice with 36Kb of the Grb10 locus replaced by a gene-trap containing a β-geo reporter cassette, to investigate the role of Grb10 in growth and its effects on metabolism. Our experiments demonstrate that maternal transmission of the deletion results in overgrowth of embryos and placentas, persisting at birth with disproportionate effects on organ size. A difference in body weight remains apparent in the adult, and a decrease in fat is evident, compared to wild type littermates. Despite Grb10 expression being reminiscent of the Igf2 expression pattern during development, our findings indicate that Grb10 acts via an Igf-independent growth axis.


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