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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Intramural Research (Z01)
Project #
1Z01DK055019-02
Application #
6432172
Study Section
(CEB)
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2000
Total Cost
Indirect Cost
Name
U.S. National Inst Diabetes/Digst/Kidney
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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