PERK eIF2alpha kinase regulates neonatal growth by controlling the expression of circulating insulin-like growth factor-I derived from the liver

Humans afflicted with the Wolcott-Rallison syndrome and mice deficient for PERK (pancreatic endoplasmic reticulum eIF2alpha kinase) show severe postnatal growth retardation. In mice, growth retardation in Perk-/- mutants is manifested within the first few days of neonatal development. Growth paramet...

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Bibliographic Details
Published in:Endocrinology (Philadelphia) 2003-08, Vol.144 (8), p.3505-3513
Main Authors: Li, Yulin, Iida, Kaori, O'Neil, Jeff, Zhang, Peichuan, Li, Sheng'ai, Frank, Ami, Gabai, Aryn, Zambito, Frank, Liang, Shun-Hsin, Rosen, Clifford J, Cavener, Douglas R
Format: Article
Language:English
Subjects:
Animals
Animals, Newborn - growth & development
Biometry
Body Weight
Cell Count
Cell Division
Chondrocytes - pathology
eIF-2 Kinase - deficiency
eIF-2 Kinase - genetics
eIF-2 Kinase - physiology
Gene Expression Regulation
Growth Disorders - genetics
Growth Disorders - prevention & control
Growth Plate - pathology
Insulin-Like Growth Factor I - administration & dosage
Insulin-Like Growth Factor I - genetics
Insulin-Like Growth Factor I - physiology
Liver - chemistry
Liver - metabolism
Mice
Mice, Knockout
Mice, Transgenic
RNA, Messenger - analysis
Tibia
Transcription, Genetic
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Summary:Humans afflicted with the Wolcott-Rallison syndrome and mice deficient for PERK (pancreatic endoplasmic reticulum eIF2alpha kinase) show severe postnatal growth retardation. In mice, growth retardation in Perk-/- mutants is manifested within the first few days of neonatal development. Growth parameters of Perk-/- mice, including comparison of body weight to length and organ weights, are consistent with proportional dwarfism. Tibia growth plates exhibited a reduction in proliferative and hypertrophic chondrocytes underlying the longitudinal growth retardation. Neonatal Perk-/- deficient mice show a 75% reduction in liver IGF-I mRNA and serum IGF-I within the first week, whereas the expression of IGF-I mRNA in most other tissues is normal. Injections of IGF-I partially reversed the growth retardation of the Perk-/- mice, whereas GH had no effect. Transgenic rescue of PERK activity in the insulin- secreting beta-cells of the Perk-/- mice reversed the juvenile but not the neonatal growth retardation. We provide evidence that circulating IGF-I is derived from neonatal liver but is independent of GH at this stage. We propose that PERK is required to regulate the expression of IGF-I in the liver during the neonatal period, when IGF-I expression is GH-independent, and that the lack of this regulation results in severe neonatal growth retardation.
ISSN:0013-7227