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Organ-specific defects in insulin-like growth factor and insulin receptor signaling in late gestational asymmetric intrauterine growth restriction in Cited1 mutant mice.
- Source :
-
Endocrinology [Endocrinology] 2011 Jun; Vol. 152 (6), pp. 2503-16. Date of Electronic Publication: 2011 Apr 12. - Publication Year :
- 2011
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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.
- Subjects :
- Animals
Apoptosis Regulatory Proteins
Brain growth & development
Brain metabolism
Disease Models, Animal
Female
Fetal Growth Retardation genetics
Gestational Age
Humans
Insulin-Like Growth Factor I genetics
Insulin-Like Growth Factor II genetics
Kidney growth & development
Kidney metabolism
Liver growth & development
Liver metabolism
Mice
Mice, Knockout
Nuclear Proteins deficiency
Organ Size
Organ Specificity
Pregnancy
Pregnancy Complications genetics
Receptor, IGF Type 1 genetics
Receptor, Insulin genetics
Trans-Activators deficiency
Fetal Growth Retardation metabolism
Insulin-Like Growth Factor I metabolism
Insulin-Like Growth Factor II metabolism
Nuclear Proteins genetics
Pregnancy Complications metabolism
Receptor, IGF Type 1 metabolism
Receptor, Insulin metabolism
Signal Transduction
Trans-Activators genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1945-7170
- Volume :
- 152
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Endocrinology
- Publication Type :
- Academic Journal
- Accession number :
- 21486933
- Full Text :
- https://doi.org/10.1210/en.2010-1385