Sci. Aging Knowl. Environ., 27 February 2002
Vol. 2002, Issue 8, p. tg1

GENETICALLY ALTERED MICE

Growth Hormone Receptor Knockout (Laron) Mice

http://sageke.sciencemag.org/cgi/content/full/sageke;2002/8/tg1


Mouse Growth hormone receptor (GHr) knockout (Laron) mice
Genetic background Life-span analysis performed on mixed 129Ola and BalbC
Gene changed GHr
Type of change Knockout
Nature of protein GHr is a 638-amino acid (precursor) transmembrane protein that binds to growth hormone (GH). Binding results in dimerization of the receptor and activation of an intracellular signaling pathway that leads to the synthesis of insulin-like growth factor-1 (IGF-1). Some of the effects of GH are IGF-1-independent; that is, certain effects of GH do not require an active IGF-1 pathway, and some effects of IGF-1 are not under the upstream control of GH.
Phenotype Small body size, stunted growth. However, unlike the Ames and Snell mice, which are sterile, fertility (in both males and females) is only slightly decreased. Homozygotes have body mass reduced by about 40%, whereas heterozygotes have only slightly decreased body weight as compared to wild-type animals.
Corresponding human phenotype GRr deficiency. The Online Mendelian Inheritance in Man (OMIM) number for GHr is *600946. Laron syndrome. The OMIM number for pituitary dwarfism II is #262500. People who suffer from Laron syndrome are slightly immunodeficient and small. There is preliminary evidence that some Laron patients have an increased life-span.
Primary reference Y. Zhou, B. C. Xu, H. G. Maheshwari, L. He, M. Reed, M. Lozykowski, S. Okada, L. Cataldo, K. Coschigamo, T. E. Wagner, J. J. Kopchick, A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mouse). Proc. Natl. Acad. Sci. U.S.A. 94, 13215-13220 (1997).
Additional references See below.
Source Contact authors of primary reference.
Other comments For more information on GHr, see below.
Other links Related transgenic/knockout mice:
Ames dwarf mice: http://sageke.sciencemag.org/cgi/content/full/sageke;2001/1/tg11
Snell dwarf mice: http://sageke.sciencemag.org/cgi/content/full/sageke;2001/3/tg13
Little mice: http://sageke.sciencemag.org/cgi/content/full/sageke;2001/4/tg14
OMIM entries for human GHr:
GHr deficiency: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?cmd=entry&id=600946
Laron syndrome: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=262500
Keywords growth hormone, growth hormone receptor, aging/ageing, life-span, Ames dwarf, Little dwarf, Snell dwarf
Prepared by Florian Muller

GHr Knockout (Laron) Mice

One of the most dynamic areas of current research in the field of aging centers on the GH/IGF-1 axis as a regulator of metabolism and longevity. Work in invertebrates suggests that putative homologs of IGF-1 are involved in the control of stress resistance and longevity. In mammals, it has been reported that Snell and Ames dwarf mice have remarkably increased life-spans (both average and maximum); however, in addition to having reduced levels of GH/IGF-1, these animals display other endocrine defects that are unrelated to GH and by themselves, or in concert with ablated GH signaling, could be responsible for the observed increase in longevity. The findings of Coschingano et al., that GHr knockout mice have a substantially increased life-span, would indicate that inhibition of the GH/IGF-1 axis is in large part responsible for the increase in life-span seen in the Ames and Snell mice. However, the cohort sample size used in the life-span determination by Coschigano et al. was very small (only 7 GHr-/- males and 11 GHr-/- females). This fact casts some doubt on the validity of the above conclusion and makes it impossible to quantitatively compare the increase in life-span observed in the Laron mice with that observed in the Ames and Snell mice. Unfortunately, the use of small sample sizes is typical in studies of life-span in rodents, especially when the work is carried out by researchers who do not specialize in studies of aging. Another problem with this study is that a mixed genetic background was used, which adds another potential confounding factor to the equation. Thus, these findings are best characterized as preliminary. Although it would be advisable to repeat this study with a larger sample size (and with genetically homogenous mice), the conclusion that a reduction in GH/IGF-1 signaling is responsible for much of the observed increase in longevity in Ames and Snell mice is probably still correct, based on the additional finding that GHRHr mutant mice (Little mice) also have an increased life-span. Life-span experiments in Little mice were carried out on a larger sample size.

Finally, in a report that should also be considered preliminary, it appears as if a subgroup of patients with Laron syndrome (caused by a mutation in the GHr gene) have an increase in average life expectancy (see Bartke, 2001, and Krzisnik, 1999). However, even assuming that eliminating GH signaling would lead to a 40% increase in maximum life-span in humans, it is doubtful that anyone would want to be subjugated to such a treatment. Aldous Huxley, who was often critical of science, wrote about a human who was made to live 150 years, but at the cost of becoming a small, hairy, apelike creature. Taking into account all the phenotypes of GHr and GHRHr knockout mice (small body size, immunodeficiency, etc.), if a human subjected him- or herself to such a fate, the imaginings of Aldous Huxley would not be too far off.

Florian Muller

February 27, 2002

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  7. Y. Zhou, B. C. Xu, H. G. Maheshwari, L. He, M. Reed, M. Lozykowski, S. Okada, L. Cataldo, K. Coschigamo, T. E. Wagner, J. J. Kopchick, A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mouse). Proc. Natl. Acad. Sci. U.S.A. 94, 13215-13220 (1997).[Abstract/Free Full Text]








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