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 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
Yulin
Y
Department of Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
Iida
Kaori
K
O'Neil
Jeff
J
Zhang
Peichuan
P
Li
Sheng'ai
S
Frank
Ami
A
Gabai
Aryn
A
Zambito
Frank
F
Liang
Shun-Hsin
SH
Rosen
Clifford J
CJ
Cavener
Douglas R
DR
D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development*; D001699:Biometry; D001835:Body Weight; D002452:Cell Count; D002455:Cell Division; D019902:Chondrocytes / Q000473:pathology; D005786:Gene Expression Regulation; D006130:Growth Disorders / Q000235:genetics / Q000517:prevention & control; D006132:Growth Plate / Q000473:pathology; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage / Q000235:genetics* / Q000502:physiology; D008099:Liver / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000032:analysis; D013977:Tibia; D014158:Transcription, Genetic; D019892:eIF-2 Kinase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D007334:Insulin-Like Growth Factor I; D012333:RNA, Messenger; D019892:eIF-2 Kinase