Insulin-like growth factor-binding protein-1 (IGFBP-1) mediates hypoxia-induced embryonic growth and developmental retardation

doi:10.1073/pnas.0407443102

Insulin-like growth factor-binding protein-1 (IGFBP-1) mediates hypoxia-induced embryonic growth and developmental retardation

^*Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109; and ^†Department of Aquatic Bioscience, Graduate School of Agricultural and Life Sciences, University of Tokyo, Bunkyo, Tokyo 113-8657, Japan

Edited by Donald F. Steiner, University of Chicago, Chicago, IL, and approved December 13, 2004 (received for review October 7, 2004)

Abstract

Although reduced fetal growth in response to hypoxia has been appreciated for decades, we have a poor understanding of the effects of hypoxia on embryonic development and the underlying cellular and molecular mechanisms. Here we show that hypoxia treatment not only resulted in embryonic growth retardation but also caused significant delay in developmental speed and the timing of morphogenesis in vital organs of zebrafish. Hypoxia strongly induced the expression of insulin-like growth factor (IGF)-binding protein (IGFBP)-1, a secreted protein that binds IGFs in extracellular environments. Hypoxia did not change the expression levels of IGFs, IGF receptors, or other IGFBPs. The hypothesis that elevated IGFBP-1 mediates hypoxia-induced embryonic growth retardation and developmental delay by binding to and inhibiting the activities of IGFs was tested by loss- and gain-of-function approaches. Knockdown of IGFBP-1 significantly alleviated the hypoxia-induced growth retardation and developmental delay. Overexpression of IGFBP-1 caused growth and developmental retardation under normoxia. Furthermore, reintroduction of IGFBP-1 to the IGFBP-1 knocked-down embryos restored the hypoxic effects on embryonic growth and development. When tested in vitro with cultured zebrafish embryonic cells, IGFBP-1 itself had no mitogenic activity, but it inhibited IGF-1- and IGF-2-stimulated cell proliferation. This inhibitory effect was abolished when IGF-1 or IGF-2 was added in molar excess, suggesting that IGFBP-1 inhibits embryonic growth and development by binding to and inhibiting the activities of IGFs. The induction of IGFBP-1 expression may be a conserved physiological mechanism to restrict the IGF-stimulated growth and developmental process under hypoxic stress.

Footnotes

↵ ‡ To whom correspondence should be addressed. E-mail: cduan{at}umich.edu.
Author contributions: S.K. and C.D. designed research; S.K. performed research; S.K., K.A., and C.D. analyzed data; and S.K. and C.D. wrote the paper.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: IUGR, intrauterine growth restriction; IGF, insulin-like growth factor; IGFBP, IGF-binding protein; HIF, hypoxia-inducible factor; MO, morpholino oligonucleotide; HTA, head–trunk angle; hpf, hours postfertilization.