In vivo analysis of growth hormone receptor signaling domains and their associated transcripts

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

125 Citations (Scopus)

Abstract

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 knock-in mouse models with deletions of specific domains of the receptor that are required for its in vivo actions. Mice expressing truncations at residue m569 (plus Y539/545-F) and at residue m391 displayed a progressive impairment of postnatal growth with receptor truncation. Moreover, after 4 months of age, marked male obesity was observed in both mutant 569 and mutant 391 and was associated with hyperglycemia. Both mutants activated hepatic JAK2 and ERK2, whereas 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.

Original languageEnglish
Pages (from-to)66-77
Number of pages12
JournalMolecular and Cellular Biology
Volume25
Issue number1
DOIs
Publication statusPublished - Jan 2005
Externally publishedYes

Bibliographical note

An erratum for this article exists in Molecular and Cellular Biology, vol. 25, no. 5, p. 2072. DOI: 10.1128/MCB.25.5.2072.2005

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