International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


Smith FM1, Charalambous M.2, Koumanov F.1, Garfield A.1, Ward A.1

1 Centre for Regenerative Medicine, University of Bath, Bath, United Kingdom, 2 Centre for Diabetes and Endocrinology, Division of Medicine, London, United Kingdom

Growth Factor Receptor-bound protein 10 (Grb10) is a member of the Grb7 family of SH2 domain-containing adaptor proteins. Murine Grb10 is maternally expressed, located on chromosome 11, and uniparental disomy (UPD) of this region results in reciprocal growth phenotypes. Grb10 has been shown to associate in vitro with a number of tyrosine kinase receptors including Igf1r and Insr, although its function and signalling remain unclear. Mice with disruption of the Grb10 locus were generated (termed Grb10D 2-4) to characterise the physiological role of this signalling protein. Maternal transmission of Grb10D 2-4 resulted in intrauterine and post-natal growth enhancement with disproportionate effects on organ size and increased liver glycogen. Despite Grb10 expression being reminiscent of the Igf2 expression pattern during development, our findings indicate that Grb10 acts via an Igf-independent growth axis. Adult mice displayed reduced adipose tissue content, mild hypoinsulinemia and improved glucose tolerance. Enhanced Insr signalling was observed in cultured adipocytes and muscle lysates of Grb10D 2-4 mice following insulin stimulation. Genetic tests confirm a tissue-specific interaction of Grb10 with the Insr to affect growth and glucose homeostasis. Our findings demonstrate that Grb10 is important in growth and provide the first in vivo evidence for a role as a modulator of insulin action.

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