In vivo analysis of gene expression in long-lived mice lacking the pregnancy-associated plasma protein A (PappA) gene.
Mice lacking the pregnancy-associated plasma protein A (PappA) gene exhibit diminished localized IGF-1 bioavailability and a 30% increase in mean life span. However, it is uncertain which tissues exhibit reduced IGF-1 signals in the PappA(-/-) mouse, and whether effects of this mutation parallel those of mutations that diminish IGF-1 in serum. Across a panel of 21 tissues, we used RT-PCR to evaluate the effects of the PappA(-/-) mutation on expression of Igfbp5, which served as an in vivo indicator of IGF-1 signaling. Among these tissues, expression of Igfbp5 was significantly reduced by PappA(-/-) only in kidney. A broader survey of IGF-associated genes in six organs identified five other genes responsive to PappA(-/-) in kidney, with stronger effects in this organ relative to other tissues. Renal expression of Irs1 and Mt1 was increased by PappA(-/-) as well as by mutations that reduce IGF-1 in serum (i.e., Ghr(-/-), Pit1(dw/dw) and Prop1(df/df)), and we demonstrate that expression of these genes is regulated by growth hormone-treatment and calorie restriction. These results provide in vivo data on an important new model of mammalian aging, and characterize both similar and contrasting expression patterns between long-lived mice with reduced local IGF-1 availability and diminished IGF-1 in serum.
Swindell
William R
WR
University of Michigan, Department of Pathology and Geriatrics Center, Ann Arbor, MI 48109-2200, USA. wswindel@umich.edu
Masternak
Michal M
MM
Bartke
Andrzej
A
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000235:genetics; D013006:Growth Hormone / Q000097:blood; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000502:physiology; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000502:physiology; D007668:Kidney / Q000378:metabolism; D008136:Longevity; D008668:Metallothionein / Q000235:genetics; D051379:Mice; D008815:Mice, Inbred Strains; D011266:Pregnancy-Associated Plasma Protein-A / Q000502:physiology*
D002352:Carrier Proteins; D006023:Glycoproteins; D055504:Insulin Receptor Substrate Proteins; D018974:Insulin-Like Growth Factor Binding Protein 4; D018975:Insulin-Like Growth Factor Binding Protein 5; C526295:Irs1 protein, mouse; C075944:insulin-like growth factor binding protein, acid labile subunit; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D008668:Metallothionein; D011266:Pregnancy-Associated Plasma Protein-A