Growth axis maturation is linked to nutrition, growth and developmental rate

Hetz, Jennifer; Menzies, Brandon R.; Shaw, Geoff; Rao, Arathi; Clarke, I. J.; Renfree, Marilyn B.

doi:10.1016/j.mce.2015.04.009

Cited by 8 publications

(2 citation statements)

References 70 publications

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“…Instead, intrauterine growth depends on IGF2 and IGF1, with the latter acting independently of GH during this period of development [51] . An essential role of GH as a postnatal growth promoter is established during the maturation of the endocrine growth axis, which is associated with an increase in expression of hepatic GHR [52] . In general, intrauterine maturation of endocrine functions in pigs is similar to humans, whereas rodents are born in a more immature state (reviewed in [53] ).…”

Section: Discussionmentioning

confidence: 99%

Growth hormone receptor-deficient pigs resemble the pathophysiology of human Laron syndrome and reveal altered activation of signaling cascades in the liver

Hinrichs

Kessler

Kurome³

et al. 2018

Molecular Metabolism

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ObjectiveLaron syndrome (LS) is a rare, autosomal recessive disorder in humans caused by loss-of-function mutations of the growth hormone receptor (GHR) gene. To establish a large animal model for LS, pigs with GHR knockout (KO) mutations were generated and characterized.MethodsCRISPR/Cas9 technology was applied to mutate exon 3 of the GHR gene in porcine zygotes. Two heterozygous founder sows with a 1-bp or 7-bp insertion in GHR exon 3 were obtained, and their heterozygous F1 offspring were intercrossed to produce GHR-KO, heterozygous GHR mutant, and wild-type pigs. Since the latter two groups were not significantly different in any parameter investigated, they were pooled as the GHR expressing control group. The characterization program included body and organ growth, body composition, endocrine and clinical-chemical parameters, as well as signaling studies in liver tissue.ResultsGHR-KO pigs lacked GHR and had markedly reduced serum insulin-like growth factor 1 (IGF1) levels and reduced IGF-binding protein 3 (IGFBP3) activity but increased IGFBP2 levels. Serum GH concentrations were significantly elevated compared with control pigs. GHR-KO pigs had a normal birth weight. Growth retardation became significant at the age of five weeks. At the age of six months, the body weight of GHR-KO pigs was reduced by 60% compared with controls. Most organ weights of GHR-KO pigs were reduced proportionally to body weight. However, the weights of liver, kidneys, and heart were disproportionately reduced, while the relative brain weight was almost doubled. GHR-KO pigs had a markedly increased percentage of total body fat relative to body weight and displayed transient juvenile hypoglycemia along with decreased serum triglyceride and cholesterol levels. Analysis of insulin receptor related signaling in the liver of adult fasted pigs revealed increased phosphorylation of IRS1 and PI3K. In agreement with the loss of GHR, phosphorylation of STAT5 was significantly reduced. In contrast, phosphorylation of JAK2 was significantly increased, possibly due to the increased serum leptin levels and increased hepatic leptin receptor expression and activation in GHR-KO pigs. In addition, increased mTOR phosphorylation was observed in GHR-KO liver samples, and phosphorylation studies of downstream substrates suggested the activation of mainly mTOR complex 2.ConclusionGHR-KO pigs resemble the pathophysiology of LS and are an interesting model for mechanistic studies and treatment trials.

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Section: Discussionmentioning

confidence: 99%

Growth hormone receptor-deficient pigs resemble the pathophysiology of human Laron syndrome and reveal altered activation of signaling cascades in the liver

Hinrichs

Kessler

Kurome³

et al. 2018

Molecular Metabolism

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“…Although very little is known about importance of GH actions in Australian marsupial physiology, with published data being limited to a few observational studies in wallaby (Hetz et al, 2015;Hetz et al, 2016;Menzies et al, 2012), remarkably two of the putative GH-stimulated Stat5b binding enhancers found in IGF1/Igf1 loci in other mammals (Rotwein, 2017a;Rotwein, 2017b) are present in koala, Tasmanian devil and wallaby. These elements are located in similar genomic positions, and share DNA sequence similarity with rat Igf1 Stat5b binding domains, R8-9 and R60-61 (Fig.…”

Section: Discussionmentioning

confidence: 99%

Characterizing the complexity of Australian marsupial insulin-like growth factor 1 genes

Rotwein

2019

Molecular and Cellular Endocrinology

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Insulin-like growth factor 1 (IGF1) actions are essential for somatic growth and tissue repair. IGF1 gene regulation is controlled by many inputs, with growth hormone playing a major role. In most mammals, the 6-exon IGF1/Igf1 gene produces multiple transcripts via independent activity of its promoters plus alternative RNA splicing and differential polyadenylation. Here, by analyzing public genomic and RNA-sequencing repositories, I have characterized three Australian marsupial IGF1 genes. Koala, Tasmanian devil, and wallaby IGF1 are more complicated than other mammals, as they contain up to 11 exons, and encode multiple mRNAs and predicted protein precursors, including potentially novel isoforms. Moreover, just two of multiple growth hormonestimulated transcriptional enhancers found in other IGF1/Igf1 loci are detected in these species. These observations define Australian marsupial IGF1 genes and demonstrate that comprehensive interrogation of genomic and RNA-sequencing resources is an effective strategy for characterizing genes and gene expression in otherwise experimentally intractable organisms.

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Metatheria: Marsupials

Renfree¹

2018

Encyclopedia of Reproduction

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Growth axis maturation is linked to nutrition, growth and developmental rate

Cited by 8 publications

References 70 publications

Growth hormone receptor-deficient pigs resemble the pathophysiology of human Laron syndrome and reveal altered activation of signaling cascades in the liver

Growth hormone receptor-deficient pigs resemble the pathophysiology of human Laron syndrome and reveal altered activation of signaling cascades in the liver

Characterizing the complexity of Australian marsupial insulin-like growth factor 1 genes

Metatheria: Marsupials

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