In vivo analysis of growth hormone receptor signaling domains and their associated transcripts.
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.
Rowland
Jennifer E
JE
Institute for Molecular Bioscience, University of Queensland, St. Lucia, Brisbane, Queensland 4072, Australia.
Lichanska
Agnieszka M
AM
Kerr
Linda M
LM
White
Mary
M
d'Aniello
Elisabetta M
EM
Maher
Sheryl L
SL
Brown
Richard
R
Teasdale
Rohan D
RD
Noakes
Peter G
PG
Waters
Michael J
MJ
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D003720:Densitometry; D005091:Exons; D005786:Gene Expression Regulation; D005838:Genotype; D006720:Homozygote; D015151:Immunoblotting; D047468:Immunoprecipitation; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008894:Milk Proteins / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008957:Models, Genetic; D009154:Mutation; D009765:Obesity / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D009929:Organ Size; D010641:Phenotype; D017434:Protein Structure, Tertiary; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D011986:Receptors, Somatotropin / Q000378:metabolism*; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D015854:Up-Regulation
D004268:DNA-Binding Proteins; D008894:Milk Proteins; D012333:RNA, Messenger; D011986:Receptors, Somatotropin; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D012313:RNA; D007334:Insulin-Like Growth Factor I; D048052:Mitogen-Activated Protein Kinase 3