Endocrine Abstracts (2006) 11 S33

Specifying the cellular responses to IGF signalling by IGF binding proteins: new lessons from the zebrafish model

C Duan


University of Michigan, Ann Arbor, MI, United States.


The insulin-like growth factor (IGF) signalling pathway plays a fundamental role in regulating growth and development. In extracellular environments, IGFs are present in complexes with high-affinity binding proteins (IGFBPs). Studies using cultured mammalian cell lines and transgenic mice suggest that IGFBPs have the ability to inhibit and/or potentiate IGF actions. Some IGFBPs may even possess intrinsic biological activities that are IGF-independent. The in vivo physiological functions of these IGFBPs, however, are poorly understood. Most research has relied on rodent models, and attempts to have been hampered by the inaccessibility of the mammalian fetus in the uterus and the greater redundancy associated with the mouse model. In recent years, there has been a remarkable acceleration in our understanding of the IGF signaling system in teleost fishes, most notably in zebrafish. To date, genes encoding for zebrafish IGF ligands, receptors, and several IGFBPs have been characterized. Taking advantage of the free-living and transparent zebrafish embryo, their expression patterns in early development have been mapped and their in vivo functions have been studied by loss- and gain-of-functional approaches. The results suggest that different IGFBPs are expressed in spatially and temporally restricted fashions and they each play distinct roles in early development. IGFBP-1 plays a key role in mediating hypoxia-caused growth and developmental retardation in zebrafish embryos. IGFBP-2 not only regulates global growth and development, but also plays a local role in vascular development. IGFBP-3 is primarily involved in the formation and differentiation of pharyngeal skeleton and inner ear, while IGFBP-5 regulates muscle and skeletal tissue differentiation. Based on these findings, a conceptual model on the role of secreted binding proteins in regulating growth factor actions is proposed and discussed.

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