Mark de Caestecker
Associate Professor of Medicine
Last active: 10/23/2018

Organ-specific defects in insulin-like growth factor and insulin receptor signaling in late gestational asymmetric intrauterine growth restriction in Cited1 mutant mice.

Novitskaya T, Baserga M, de Caestecker MP
Endocrinology. 2011 152 (6): 2503-16

PMID: 21486933 · PMCID: PMC3100618 · DOI:10.1210/en.2010-1385

Late gestational placental insufficiency resulting in asymmetric intrauterine organ growth restriction (IUGR) is associated with an increased incidence of diabetes, cardiovascular and renal disease in adults. The molecular mechanisms mediating these defects are poorly understood. To explore this, we investigated the mechanisms leading to IUGR in Cited1 knockout mice, a genetic model of late gestational placental insufficiency. We show that loss of placental Cited1 leads to asymmetric IUGR with decreased liver, lung, and kidney sizes and preservation of fetal brain weight. IGF and insulin signaling regulate embryonic organ growth. IGF-I and IGF-II protein and mRNA expression are reduced in livers, lungs, and kidneys of embryonic d 18.5 embryos with IUGR. Decreased IGF-I is associated with reduced activating phosphorylation of the type 1 IGF receptor (pIGF-IR) in the kidney, whereas reduced IGF-II is associated with decreased phosphorylation of the insulin receptor (pIR) in the lung. In contrast, decreased pIR is associated with reduced IGF-I but not IGF-II in the liver. However, pancreatic β-cell mass and serum insulin levels are also decreased in mice with IUGR, suggesting that hepatic IR signaling may be regulated by alterations in fetal insulin production. These findings contrast with observations in IUGR fetal brains in which there is no change in IGF-IR/IR phosphorylation, and IGF-I and IGF-II expression is actually increased. In conclusion, IUGR disrupts normal fetal IGF and insulin production and is associated with organ-specific defects in IGF-IR and IR signaling that may regulate asymmetric IUGR in late gestational placental insufficiency.

MeSH Terms (22)

Animals Brain Disease Models, Animal Female Fetal Growth Retardation Gestational Age Humans Insulin-Like Growth Factor I Insulin-Like Growth Factor II Kidney Liver Mice Mice, Knockout Nuclear Proteins Organ Size Organ Specificity Pregnancy Pregnancy Complications Receptor, IGF Type 1 Receptor, Insulin Signal Transduction Trans-Activators

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