Alteration of IGF system gene expression during the postnatal development of pcd mice

Zhang, W.; Ghetti, Bernardino; Yang, Xiaolin; Lee, W. H.

doi:10.1677/joe.0.1630191

Cited by 10 publications

(6 citation statements)

References 28 publications

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“…Expression of serum IGF binding proteins (IGFBPs) was also measured. As observed previously by ligand blotting, the major IGFBPs expressed in the serum of neonatal mice are IGFBP2 and IGFBP3 23. Whereas IGFBP2 expression dominates in the early postnatal period, its serum concentration declines after PN14 in WT mice (Fig.…”

Section: Resultssupporting

confidence: 73%

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Cell non-autonomous regulation of hepatic IGF-1 and neonatal growth by Kinase Suppressor of Ras 2 (KSR2)

Guo

Costanzo-Garvey

Smith

et al. 2016

Sci Rep

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Individuals with poor postnatal growth are at risk for cardiovascular and metabolic problems as adults. Here we show that disruption of the molecular scaffold Kinase Suppressor of Ras 2 (KSR2) causes selective inhibition of hepatic GH signaling in neonatal mice with impaired expression of IGF-1 and IGFBP3. ksr2−/− mice are normal size at birth but show a marked increase in FGF21 accompanied by reduced body mass, shortened body length, and reduced bone mineral density (BMD) and content (BMC) first evident during postnatal development. However, disrupting FGF21 in ksr2−/− mice does not normalize mass, length, or bone density and content in fgf21−/−ksr2−/− mice. Body length, BMC and BMD, but not body mass, are rescued by infection of two-day-old ksr2−/− mice with a recombinant adenovirus encoding human IGF-1. Relative to wild-type mice, GH injections reveal a significant reduction in JAK2 and STAT5 phosphorylation in liver, but not in skeletal muscle, of ksr2−/− mice. However, primary hepatocytes isolated from ksr2−/− mice show no reduction in GH-stimulated STAT5 phosphorylation. These data indicate that KSR2 functions in a cell non-autonomous fashion to regulate GH-stimulated IGF-1 expression in the liver of neonatal mice, which plays a key role in the development of body length.

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Section: Resultssupporting

confidence: 73%

“…Washed blots were visualized by autoradiography. The major IGFBPs expressed in mouse serum were identified by their electrophoretic mobility based on precedent23.…”

Section: Methodsmentioning

confidence: 99%

Cell non-autonomous regulation of hepatic IGF-1 and neonatal growth by Kinase Suppressor of Ras 2 (KSR2)

Guo

Costanzo-Garvey

Smith

et al. 2016

Sci Rep

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“…The low IGF-l levels are thought to contribute to the neurodegeneration of cerebellar neurons. For example, we found reduced levels of hepatic IGF-I mRNA and circulating IGF-I in weaver mutant mice [20] as well as Purkinje cell degeneration mice [23,24]. Both mouse models have cerebellar ataxia but the etiology is caused by the death of different cerebellar neuronal populations.…”

Section: Discussionmentioning

confidence: 83%

Role of the GH/IGF-I axis in the growth retardation of weaver mice

Yao

Bethin

Yang

et al. 2007

Endocr

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IGF-I is a well-established anabolic growth factor essential for growth and development. 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 mutant mouse is a commonly used model for studying hereditary cerebellar ataxia and provides an opportunity to investigate the function of IGF-I in postnatal growth following neurodegeneration. Previously, we reported that weaver mice are growth retarded and their body weights correlate with a decrease in circulating IGF-I levels. Because weaver mice have the same food intake/body weight ratios as their wild type littermates, our observation suggests that an impairment of the GH/IGF-I axis, rather than poor nutrition, likely contributes to their growth retardation. This study further investigated the etiology of reduced circulating IGF-I levels. We found that GH levels in weaver mice were reduced following acute insulin injection, but the hepatic GH receptor transduction pathway signaled normally as evidenced by increased STAT5b phosphorylation and IGF-I mRNA levels in response to acute GH administration. In addition, 2-week GH treatment induced a significant increase in body weight and circulating IGF-I levels in homozygous weaver mice but not in wild type littermates. In summary, a deficiency in the GH/IGF-I axis may be partially responsible for postnatal growth retardation in weaver mutant mice. This deficiency may occur at the level of the pituitary and/or hypothalamus and can be improved with GH administration.

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“…The pcd mouse has been considered as an important model for understanding of cerebellar degeneration and for the evaluation of new therapies such as grafting or administration of insulin-like growth factor 1 (IGF-1) [151][152][153]. This latter strategy is supported by the observation that IGF-1 mRNA expression drops in cerebellar Purkinje cells of pcd mouse as neurons undergo apoptosis [154]. At least ten independent phenotypic alleles of pcd have been identified so far, most studies having been performed with the pcd 1J , pcd 3J , and pcd 5J mice.…”

Section: Models Of Hereditary Ataxiasmentioning

confidence: 99%

Animal Models of Human Cerebellar Ataxias: a Cornerstone for the Therapies of the Twenty-First Century

Manto

Marmolino

2009

Cerebellum

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Cerebellar ataxias represent a group of disabling neurological disorders. Our understanding of the pathogenesis of cerebellar ataxias is continuously expanding. A considerable number of laboratory animals with neurological mutations have been reported and numerous relevant animal models mimicking the phenotype of cerebellar ataxias are becoming available. These models greatly help dissecting the numerous mechanisms of cerebellar dysfunction, a major step for the assessment of therapeutics targeting a given deleterious pathway and for the screening of old or newly synthesized chemical compounds. Nevertheless, differences between animal models and human disorders should not be overlooked and difficulties in terms of characterization should not be occulted. The identification of the mutations of many hereditary ataxias, the development of valuable animal models, and the recent identifications of the molecular mechanisms underlying cerebellar disorders represent a combination of key factors for the development of anti-ataxic innovative therapies. It is anticipated that the twenty-first century will be the century of effective therapies in the field of cerebellar ataxias. The animal models are a cornerstone to reach this goal.

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Alteration of IGF system gene expression during the postnatal development of pcd mice

Cited by 10 publications

References 28 publications

Cell non-autonomous regulation of hepatic IGF-1 and neonatal growth by Kinase Suppressor of Ras 2 (KSR2)

Cell non-autonomous regulation of hepatic IGF-1 and neonatal growth by Kinase Suppressor of Ras 2 (KSR2)

Role of the GH/IGF-I axis in the growth retardation of weaver mice

Animal Models of Human Cerebellar Ataxias: a Cornerstone for the Therapies of the Twenty-First Century

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