University of Bath
Grbl0 is a maternally expressed gene that encodes an intracellular signaling molecule of the SH2 domain-containing adapter family. In the mouse, Grbl0 is located on proximal chromosome 11. Mice with uniparental disomies (UPD) of this region exhibit reciprocal growth phenotypes, with overgrowth resulting from paternal UPD and growth retardation resulting from maternal UPD. The equivalent human chromosomal region (7pl1.2-p13) is associated with Silver-Russell syndrome, with features that include maternal LTD and growth retardation. Thus, Grbl0 is a candidate growth inhibitory protein and is likely to act by interacting with phosphorylated tyrosine kinase receptors. In order to assess Grbl0 function in vivo we have generated mice with a disrupted Grb10 gene. A LacZ reporter gene insertion shows that Grb10 is imprinted in most, but not all, of its sites of expression. Following maternal transmission of the mutation both the fetus and placenta exhibit overgrowth, with disproportionate effects on organ size. Grbl0 has been shown to be capable of interacting with the insulin and insulin-like growth factor (IGF) type I receptors in in vitro assays. We find that the ontogeny of the overgrowth effects in Grbl0 mutants approximately mirrors that of IGF action during development. Despite this, we present evidence that Grbl0 acts, at least in part, via a pathway that is independent of IGFs.