Sci. Aging Knowl. Environ., 26 February 2003
Vol. 2003, Issue 8, p. tg1

GENETICALLY ALTERED MICE

Igf1r+/- Mice

http://sageke.sciencemag.org/cgi/content/full/sageke;2003/8/tg1


Mouse Igf1r+/- mice
Genetic background 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.
Gene changed 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 {alpha} and {beta} subunits of IGF-1R. IGF-IR is overexpressed in many malignancies, where it functions as an anti-apoptotic agent by enhancing cell survival.
Phenotype 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.
Primary references 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).
Additional references See below.
Source Authors of primary references.
Other comments None
Other links 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
http://sageke.sciencemag.org/cgi/content/full/sageke;2002/42/tg11
Ames Dwarf mice
http://sageke.sciencemag.org/cgi/content/full/sageke;2001/1/tg11
Growth hormone receptor knockout (Laron) mice
http://sageke.sciencemag.org/cgi/content/full/sageke;2002/8/tg1
Little mice
http://sageke.sciencemag.org/cgi/content/full/sageke;2001/4/tg14
Snell Dwarf mice
http://sageke.sciencemag.org/cgi/content/full/sageke;2001/3/tg13
SAGE KE's Genes/Interventions database:
IGF-1R
http://sageke.sciencemag.org/cgi/genedata/sagekeGdbGene;287
Growth hormone receptor
http://sageke.sciencemag.org/cgi/genedata/sagekeGdbGene;246
Human growth hormone therapy
http://sageke.sciencemag.org/cgi/genedata/sagekeGdbIntrvn;71
Keywords insulin-like growth factor, insulin-like growth factor receptor, growth hormone
Prepared by Jennifer Fuller


February 26, 2003
  1. 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]
  2. 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]
  3. 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]
Citation: Igf1r+/- Mice. Science's SAGE KE (26 February 2003), http://sageke.sciencemag.org/cgi/content/full/sageke;2003/8/tg1








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