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Molecular and Cellular Biology, January 2005, p. 66-77, Vol. 25, No. 1
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.1.66-77.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

In Vivo Analysis of Growth Hormone Receptor Signaling Domains and Their Associated Transcripts

Jennifer E. Rowland,1,2,{dagger} Agnieszka M. Lichanska,1,{dagger} Linda M. Kerr,1 Mary White,2 Elisabetta M. d’Aniello,1 Sheryl L. Maher,1 Richard Brown,1 Rohan D. Teasdale,1 Peter G. Noakes,2 and Michael J. Waters1*

Institute for Molecular Bioscience,1 School of Biomedical Sciences, University of Queensland, St. Lucia, Queensland, Australia2

Received 16 June 2004/ Returned for modification 4 August 2004/ Accepted 23 September 2004

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.

* Corresponding author. Mailing address: Institute for Molecular Bioscience, University of Queensland, St. Lucia, Brisbane, Queensland 4072, Australia. Phone: (61) 7-33462037. Fax: (61) 7-33462101. E-mail: m.waters{at}uq.edu.au.

{dagger} J.E.R. and A.M.L. contributed equally to this study.

Molecular and Cellular Biology, January 2005, p. 66-77, Vol. 25, No. 1
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.1.66-77.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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