PERK eIF2alpha kinase regulates neonatal growth by controlling the expression of circulating insulin-like growth factor-I derived from the liver.
Biometry, Body-Weight, Cell-Count, Cell-Division, Chondrocytes, Gene-Expression-Regulation, Growth-Disorders, Growth-Plate, Insulin-Like-Growth-Factor-I, Liver, Mice-Knockout, Mice-Transgenic, RNA-Messenger, Tibia, Transcription-Genetic
Endocrinology 2003 Aug; 144(8):3505-3513.
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.
Li, Y; Iida, K; O'Neil, J; Zhang, P; Li, S; Frank, A; Gabai, A; Zambito, F; Liang, S H.; Rosen, C J.; and Cavener, D R., " PERK eIF2alpha kinase regulates neonatal growth by controlling the expression of circulating insulin-like growth factor-I derived from the liver." (2003). Faculty Research 2000 - 2009. 591.