PERK eIF2α kinase regulates neonatal growth by controlling the expression of circulating insulin-like growth factor-I derived from the liver

Yulin Li, Kaori Iida, Jeff O'Neil, Peichuan Zhang, Sheng'ai Li, Ami Frank, Aryn Gabai, Frank Zambito, Shun Hsin Liang, Clifford J. Rosen, Douglas R. Cavener

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

Humans afflicted with the Wolcott-Rallison syndrome and mice deficient for PERK (pancreatic endoplasmic reticulum eIF2α 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 β-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.

Original languageEnglish (US)
Pages (from-to)3505-3513
Number of pages9
JournalEndocrinology
Volume144
Issue number8
DOIs
StatePublished - Aug 1 2003

All Science Journal Classification (ASJC) codes

  • Endocrinology

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