Jennifer E. Rowland, Agnieszka M. Lichanska, Linda M. Kerr, Mary White, Elisabetta d'Aniello, Sheryl L. Maher, Richard Brown, Rohan D. Teasdale, Peter G. Noakes, and Michael J. Waters.

The growth hormone receptor (GHR) is a critical regulator of postnatal growth and metabolism. However, the GHR signaling domains and pathways that regulate these processes in vivo are not defined. We report the first transgenic mouse models with deletions of specific domains of the receptor that are required for its in vivo actions. Mice expressing truncations at residue 569 (plus Y539/545-F) and at residue 391 displayed a progressive impairment of postnatal growth with receptor truncation. Moreover, after 4 months of age marked obesity was observed in both 569 and 391 mutants, and was associated with hyperglycemia. Both mutants activated hepatic JAK2 and ERK2, whilst STAT5 phosphorylation was substantially decreased for mutant 569 and absent from mutant 391, correlating with loss of IGF-1 expression and reduction in growth. Microarray analysis of these and GHR-/- mice demonstrated that particular signaling domains are responsible for the regulation of different target genes, and revealed novel actions of growth hormone. These mice represent the first step in delineating the domains of the GHR regulating body growth and composition, and the transcripts associated with these domains.

Supplemental information for this MCB paper describing the GHR knock-in mice is provided here as a pdf file.