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Claus Oxvig

Duplication and Diversification of the Hypoxia-Inducible IGFBP-1 Gene in Zebrafish

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  • Hiroyasu Kamei, Dept. Molecular, Cellular, and Developmental Biology, University of Michigan, United States
  • Ling Lu, Laboratory of Molecular Medicine, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China, United States
  • Shuang Jiao, Laboratory of Molecular Medicine, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China, United States
  • Yun Li, Laboratory of Molecular Medicine, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China, United States
  • Claus Gyrup Nielsen, Denmark
  • Lisbeth Schmidt Laursen
  • Claus Oxvig
  • Jianfeng Zhou, Dept. Molecular, Cellular, and Developmental Biology, University of Michigan, United States
  • Cunming Duan, Dept. Molecular, Cellular, and Developmental Biology, University of Michigan, United States
Background: Gene duplication is the primary force of new gene evolution. Deciphering whether a pair of duplicated genes has evolved divergent functions is often challenging. The zebrafish is uniquely positioned to provide insight into the process of functional gene evolution due to its amenability to genetic and experimental manipulation and because it possess a large number of duplicated genes.
Methodology/Principal Findings: We report the identification and characterization of two hypoxia-inducible genes in zebrafish that are co-ortholgs of human IGF binding protein-1 (IGFBP-1). IGFBP-1 is a secreted protein that binds to IGF and modulates IGF actions in somatic growth, development, and aging. Like their human and mouse counterparts, in adult
zebrafish igfbp-1a and igfbp-1b are exclusively expressed in the liver. During embryogenesis, the two genes are expressed in overlapping spatial domains but with distinct temporal patterns. While zebrafish IGFBP-1a mRNA was easily detected throughout embryogenesis, IGFBP-1b mRNA was detectable only in advanced stages. Hypoxia induces igfbp-1a expression in early embryogenesis, but induces the igfbp-1b expression later in embryogenesis. Both IGFBP-1a and -b are capable of IGF binding, but IGFBP-1b has much lower affinities for IGF-I and -II because of greater dissociation rates. Overexpression of
IGFBP-1a and -1b in zebrafish embryos caused significant decreases in growth and developmental rates. When tested in cultured zebrafish embryonic cells, IGFBP-1a and -1b both inhibited IGF-1-induced cell proliferation but the activity of IGFBP-1b was significantly weaker.

Conclusions/Significance: These results indicate subfunction partitioning of the duplicated IGFBP-1 genes at the levels of gene expression, physiological regulation, protein structure, and biological actions. The duplicated IGFBP-1 may provide additional flexibility in fine-tuning IGF signaling activities under hypoxia and other catabolic conditions.
Original languageEnglish
JournalP L o S One
Volume3
Issue8
Pages (from-to)e3091
Number of pages13
ISSN1932-6203
DOIs
Publication statusPublished - Dec 2008

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