50 Role of the GH/IGF-I Axis in the Growth Retardation of Weaver Mice

Abstract

IGF-I is an anabolic growth factor essential for growth and development, both as a mediator of growth hormone (GH) action and as a growth factor for cell proliferation and differentiation. Although the role of the GH/IGF-I axis is established for normal postnatal growth, its functional state in neurodegenerative diseases is not fully characterized. The weaver (wv) mutant mouse is a commonly used model for studying hereditary cerebellar ataxia and provides an opportunity to study the function of IGF-I in postnatal growth during neurodegeneration. Previously, we reported that weaver mice are growth retarded and their body weights correlate with a decrease in circulating IGF-I levels, suggesting that IGF-I's endocrine function is impaired in weaver mice. This study further investigated the cause of lower circulating IGF-I levels. Most circulating IGF-I is synthesized in the liver under the control of GH. We found that GH levels in wv mice are reduced, but the hepatic GH receptor signal transduction pathway functions normally, because acute GH treatment increased STAT5b phosphorylation and IGF-I mRNA levels in weaver mice. To investigate whether decreased circulating GH contributes to wv mouse growth retardation, we treated weaver mice with GH for 2 weeks and found a signify cant increase in body weights and circulating IGF-I levels in weaver mice, but not in wild type mice. In summary, our results suggest that postnatal growth retardation in weaver mutant mice likely results from a dysfunction in the GH/IGF-I axis.