Organ-Specific Defects in Insulin-Like Growth Factor and Insulin Receptor Signaling in Late Gestational Asymmetric Intrauterine Growth Restriction in Cited1 Mutant Mice

Abstract

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.

Maternal protein restriction induces alterations in insulin signaling and ATP sensitive potassium channel protein in hypothalami of intrauterine growth restriction fetal rats

“…There was no change in the expression and phosphorylation level of IR, in line with the observations in asymmetric IUGR fetal brain in Cited1 mutant mice. (33) The results also indicated that maternal protein-restriction caused the reduced expression of SUR1 in the fetal hypothalamus. In SUR1 null mice, insulin’s ability to suppress hepatic gluconeogenesis was impaired.…”

Imprinted genes in mouse placental development and the regulation of fetal energy stores

“…Vascularisation of the labyrinth was defective, with increased sinusoidal spaces resulting in a reduced surface area for nutrient transport (Rodriguez et al 2004). Consistent with placental insufficiency, mutant embryos were asymmetrically growth restricted during late gestation, with the majority of mutants dying in the neonatal period and survivors exhibiting catch-up growth within 8 weeks of birth (Rodriguez et al 2004, Novitskaya et al 2011.…”

A genomic atlas of human adrenal and gonad development

“…Cited1 knockout mice have growth restriction, late placental insufficiency and abnormalities in nephron patterning and pubertal mammary ductal morphogenesis (Howlin et al, 2006; Novitskaya et al, 2011; Plisov, 2005; Rodriguez et al, 2004). Although Cited1 was identified as a target of Sry in one mouse ChIP-CHIP study (Li et al, 2014), little is known about Cited1 in mouse testis.…”