Sci. Aging Knowl. Environ., 26 February 2003
Vol. 2003, Issue 8, p. tg1
GENETICALLY ALTERED MICE
||ES cells: 129SvEvTac
F0 = MeuCre transgenic line x IGF-IRneolox (both C57BL/6),
F1 = Cre-lox double transgenic (C57BL/6) x homozygous IGF-IRneolox (129/Sv)
F2 = six different genotypes with a large range of receptor deficiencies [measured as a percentage of the wild type (WT)]. The Igf1r-/- phenotype is perinatal lethal.
||Igf-1r, insulin-like growth factor type 1 receptor (IGF-1R, also known as CD221). The Igf1-r gene contains 21 exons and spans about 100 kb.
|Type of change
||Targeted mutation of WT Igf-1r gene exon 3. Exon 3 was replaced by a floxed version of exon 3 with a neomycin resistance cassette. A third loxP site was also co-introduced into exon 2.
|Nature of protein
||IGF-1R binds insulin-like growth factor with high affinity, has tyrosine kinase activity, and plays a critical role in transformation events. Cleavage of the precursor protein generates the and subunits of IGF-1R. IGF-IR is overexpressed in many malignancies, where it functions as an anti-apoptotic agent by enhancing cell survival.
||Although Igf1r-/- mice display numerous abnormalities, including perinatal lethality, Igf1r+/- mice exhibit only varying levels of growth retardation dependent on the level of the IGF-1R gene deficiency. These modest weight differences are noted only after the weaning period ( Igf1r+/- mice are of normal birth weight) and affect all tissues to a similar level throughout the duration of their lives. Female Igf1r+/- mice lived 33% longer than their female control littermates, whereas male Igf1r+/- mice lived only 16% longer than normal males. All Igf1r+/- mice have an augmented resistance to oxidative stress, which may be a factor in the longer life-span of these mice.
|Corresponding human phenotype
||Patients with embryonal tumors (Wilms tumor, hepatoblastoma, and adrenal tumors) generally show expression of IGF-1R from only one allele. There is a significant association between high IGF-1R expression and death from metastatic disease, possibly because IGF-1R production occurs mainly in the liver, the preferential site for uveal melanoma metastases.
||M. Holzenberger, G. Hamard, R. Zaoui, P. Leneuve, B. Ducos, C. Beccavin, L. Perin, Y. Le Bouc, Experimental IGF-1 receptor deficiency generates a sexually dimorphic pattern of organ-specific growth deficits in mice, affecting fat tissue in particular. Endocrinology 142, 4469-4478 (2001); M. Holzenberger, J. Dupont, B. Ducos, P. Leneuve, A. Geloen, P. C. Even, P. Cervera, Y. Le Bouc, IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421, 182-187 (2003).
||Authors of primary references.
||Online Mendelian Inheritance in Man (OMIM) entries for related human conditions:
Wilms tumor http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?194070
Related transgenic/knockout mice:
Liver-specific IGF-1-deficient mice
Ames Dwarf mice
Growth hormone receptor knockout (Laron) mice
Snell Dwarf mice
SAGE KE's Genes/Interventions database:
Growth hormone receptor
Human growth hormone therapy
||insulin-like growth factor, insulin-like growth factor receptor, growth hormone
February 26, 2003
- J.-P. Liu, J. Baker, A. S. Perkins, E. J. Robertson, A. Efstratiadis, Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 75, 59-72 (1993).[Medline]
- A. M. Fernandez, J. K. Kim, S. Yakar, J. Dupont, C. Hernandez-Sanchez, A. L. Castle, J. Filmore, G. I. Shulman, D. Le Roith, Functional inactivation of the IGF-I and insulin receptors in skeletal muscle causes type 2 diabetes. Genes Dev. 15, 1926-1934 (2001). [Abstract/Free Full Text]
- M. Holzenberger, J. Dupont, B. Ducos, P. Leneuve, A. Geloen, P. C. Even, P. Cervera, Y. Le Bouc, IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421, 182-187 (2003). [CrossRef][Medline]
Mice. Science's SAGE KE
(26 February 2003), http://sageke.sciencemag.org/cgi/content/full/sageke;2003/8/tg1