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
Department of Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
Endocrinology. 2003 Aug;144(8):3505-13. doi: 10.1210/en.2003-0236.
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.
患有沃尔科特-拉利森综合征的人类以及PERK（胰腺内质网eIF2α激酶）缺陷的小鼠表现出严重的出生后生长迟缓。在小鼠中，Perk-/-突变体的生长迟缓在新生儿发育的最初几天内就会显现出来。Perk-/-小鼠的生长参数，包括体重与体长的比较以及器官重量，与比例性侏儒症一致。胫骨生长板显示纵向生长迟缓背后的增殖性和肥大性软骨细胞减少。新生的Perk-/-缺陷小鼠在第一周内肝脏IGF-I mRNA和血清IGF-I降低了75%，而大多数其他组织中IGF-I mRNA的表达正常。注射IGF-I部分逆转了Perk-/-小鼠的生长迟缓，而生长激素没有效果。在Perk-/-小鼠的胰岛素分泌β细胞中对PERK活性进行转基因拯救逆转了幼年但不是新生儿的生长迟缓。我们提供证据表明循环中的IGF-I来自新生儿肝脏，但在这个阶段独立于生长激素。我们提出，在新生儿期，当IGF-I的表达不依赖于生长激素时，PERK是调节肝脏中IGF-I表达所必需的，并且这种调节的缺乏导致严重的新生儿生长迟缓。
