The insulin-like growth factors (IGFs) play essential roles in pre-natal and post-natal growth and development. In rodents, IGF- I is widely expressed and homozygous null mutants result in fetal growth retardation, peri-natal mortality and growth retardation, and infertility in surviving offspring. There remains, however, a fundamental question regarding the role of circulating (endocrine form) IGF-I in growth and development versus the local tissue production of IGF-I (autocrine/paracrine form). To answer this question, we have used the homologous recombination technique that utilizes the Cre recombinase/loxP system. The loxP sequences were introduced into the mouse genome flanking exon 4 of the IGF-I gene. These mice were mated with mice expressing Cre exclusively in the liver; the Cre cDNA being driven by the albumin promoter. Exon 4 of the IGF-I gene was totally deleted as seen on Southern blot analysis, and IGF-I mRNA was no greater than 2 percent of wild-type littermates, as shown by Solution hybridization/RNase protection assay. Despite the reduction in circulating IGF-I levels, these animals showed normal growth and development over the 6 to 8 weeks of post-natal development. IGF-I mRNA levels in extra-hepatic tissues, including kidney and fat, were not increased in the homozygous IGF-I-depleted animals. These findings suggest that while the liver is a major source of circulating IGF-I, normal post-natal growth and development can occur in the absence of hepatic IGF-I production. Studies are on-going to test the role of paracrine/autocrine IGF-I in growth and development. Liver-specific IGF-I gene deleted mice are being crossed with mice that have no fat to determine whether fat tissue releases IGF-I into the circulation, and with acid labile subunit (ALS) gene-deleted mice to reduce the protection of IGF-I in the circulation, thereby reducing circulating IGF-I levels further, and determine this effect on growth and development. Using these mice, we are testing whether the reduced circulating IGF-I levels affect breast cancer development in SVT Ag transgenic mice and the metastases of colonic cancer implanted into the cecal area.
| Yakar, Shoshana; Pennisi, Patricia; Wu, Yiping et al. (2005) Clinical relevance of systemic and local IGF-I. Endocr Dev 9:11-6 |
| Yakar, Shoshana; Leroith, Derek; Brodt, Pnina (2005) The role of the growth hormone/insulin-like growth factor axis in tumor growth and progression: Lessons from animal models. Cytokine Growth Factor Rev 16:407-20 |
| Yakar, Shoshana; Pennisi, Patricia; Zhao, Hong et al. (2004) Circulating IGF-1 and its role in cancer: lessons from the IGF-1 gene deletion (LID) mouse. Novartis Found Symp 262:3-9; discussion 9-18, 265-8 |
| Yakar, Shoshana; Setser, Jennifer; Zhao, Hong et al. (2004) Inhibition of growth hormone action improves insulin sensitivity in liver IGF-1-deficient mice. J Clin Invest 113:96-105 |
| Wu, Yiping; Cui, Karen; Miyoshi, Keiko et al. (2003) Reduced circulating insulin-like growth factor I levels delay the onset of chemically and genetically induced mammary tumors. Cancer Res 63:4384-8 |
