Insulin-like growth factor-binding protein-3 plays an important role in regulating pharyngeal skeleton and inner ear formation and differentiation
Insulin-like growth factor-binding protein-3 plays an important role in regulating pharyngeal skeleton and inner ear formation and differentiation
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DOI：
10.1074/jbc.m411479200
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发表时间：
2005-02-04
影响因子：
4.8
通讯作者：
Duan, CM
中科院分区：
文献类型：
--
作者：
Li, Y;Xiang, JH;Duan, CM
胰岛素样生长因子结合蛋白（IGFBP）-3是血液中主要的胰岛素样生长因子（IGF）载体蛋白。IGFBP-3延长循环IGF的半衰期，并阻止其潜在的降血糖作用。IGFBP-3也在胎儿和成人阶段的许多外周组织中表达。在体外，IGFBP-3可以抑制或增强IGF的作用，甚至具有IGF非依赖性活性，表明局部IGFBP-3也可能具有旁分泌/自分泌功能。然而，IGFBP-3的体内功能尚不清楚。在这项研究中，我们阐明了IGFBP-3的发育作用，使用斑马鱼模型。IGFBP-3 mRNA表达首先在迁移的脑神经嵴细胞中检测到，随后在斑马鱼胚胎的咽弓中检测到。IGFBP-3 mRNA在发育中的内耳中也持续表达。为了确定IGFBP-3在这些组织中的作用，我们使用吗啉代修饰的反义寡核苷酸（MO）消融IGFBP-3基因产物。IGFBP-3基因敲除的胚胎具有延迟的咽骨骼形态发生和大大减少的咽软骨分化。IGFBP-3的敲低也显著减小内耳大小，破坏毛细胞分化和半规管形成。此外，重新引入MO抗性形式的IGFBP-3“拯救”了MO诱导的缺陷。这些结果表明IGFBP-3在调节斑马鱼咽软骨和内耳的发育和生长中起重要作用。
Insulin-like growth factor-binding protein (IGFBP)-3 is the major insulin-like growth factor (IGF) carrier protein in the bloodstream. IGFBP-3 prolongs the half-life of circulating IGFs and prevents their potential hypo-glycemic effect. IGFBP-3 is also expressed in many peripheral tissues in fetal and adult stages. In vitro, IGFBP-3 can inhibit or potentiate IGF actions and even possesses IGF-independent activities, suggesting that local IGFBP-3 may also have paracrine/autocrine function(s). The in vivo function of IGFBP-3, however, is unclear. In this study, we elucidate the developmental role of IGFBP-3 using the zebrafish model. IGFBP-3 mRNA expression is first detected in the migrating cranial neural crest cells and subsequently in pharyngeal arches in zebrafish embryos. IGFBP-3 mRNA is also persistently expressed in the developing inner ears. To determine the role of IGFBP-3 in these tissues, we ablated the IGFBP-3 gene product using morpholino-modified antisense oligonucleotides (MOs). The IGFBP-3 knocked down embryos had delayed pharyngeal skeleton morphogenesis and greatly reduced pharyngeal cartilage differentiation. Knockdown of IGFBP-3 also significantly decreased inner ear size and disrupted hair cell differentiation and semicircular canal formation. Furthermore, reintroduction of a MO-resistant form of IGFBP-3 "rescued" the MO-induced defects. These findings suggest that IGFBP-3 plays an important role in regulating pharyngeal cartilage and inner car development and growth in zebrafish.