Structural, gene expression, and functional analysis of the fugu (Takifugu rubripes) insulin-like growth factor binding protein-4 gene

Abstract

The insulin-like growth factor (IGF) signaling pathway is a conserved pathway that regulates animal development, growth, metabolism, reproduction, and aging. The biological actions of IGFs are modulated by IGF-binding proteins (IGFBPs). Although the structure and function of fish IGFBP-1, -2, -3, and -5 have been elucidated, there is currently no report on the full-length structure of a fish IGFBP-4 nor its biological action. In this study, we cloned and characterized the IGFBP-4 gene from fugu. Sequence comparison, phylogenetic, and synteny analyses indicate that its chromosomal location, gene, and protein structure are similar to its mammalian orthologs. Fugu IGFBP-4 mRNA was easily detectable in all adult tissues examined with the exception of spleen. Older animals tended to have higher levels of IGFBP-4 mRNA in the muscle and eyes compared with younger animals. Starvation resulted in significant increases in IGFBP-4 mRNA abundance in the muscle, liver, gallbladder, and brain. Overexpression of fugu and human IGFBP-4 in zebrafish embryos caused a significant decrease in body size and somite number, suggesting that fugu IGFBP-4 inhibits growth and development, possibly by binding to IGFs and inhibiting their binding to the IGF receptors. These results provide new information about the structural and functional conservation, expression patterns, and physiological regulation of the IGFBP-4 gene in a teleost fish.

Transcriptional Regulation of the IGF Signaling Pathway by Amino Acids and Insulin-Like Growth Factors during Myogenesis in Atlantic Salmon

“…3A), consistent with IGFBP-2 being a negative regulator of growth [18]. IGFBP-4 has recently been shown to be a negative regulator of growth when overexpressed in zebrafish embryos [60]. We found IGFBP-4 expression peaked at 8 d (Fig.…”

Effects of phytoestrogens on growth-related and lipogenic genes in rainbow trout (Oncorhynchus mykiss)

“…In mammals the growthpromoting effects of IGFBP5 are attributed to its high binding affinity for the extracellular matrix, which reduces its affinity for IGF1 and IGF2 by approximately 15-fold, possibly potentiating the binding of the IGF peptides to IGF receptors on the cell surface (Clemmons, 1998;Duan and Xu, 2005). However, evidence suggests IGFBP4 is a functional antagonist of IGF1 (Wang et al, 1998;Li et al, 2009) and inhibits myogenesis (Grzelkowska-Kowalczyk et al, 2013), suggesting a catabolic effect on growth. In some fish igfbp4 expression is positively correlated with growth performance (Bower et al, 2008;Safian et al, 2012), which introduces potential for species-specific effects of IGFBP4 on myogenesis.…”

Variation in branchial expression among insulin-like growth-factor binding proteins (igfbps) during Atlantic salmon smoltification and seawater exposure

“…The function of Igfbp4, at least in mammals, highly depends on the physiological context surrounding its production, and may operate as either a stimulator or inhibitor of Igf1/2 signaling [57, 58]. The activities of a teleost Igfbp4 were first assessed in fugu ( Takifugu rubripes ) where overexpression delayed embryonic development [59]. Nonetheless, in Atlantic salmon and sea bream ( Sparus aurata ), igfbp4 expression is implicated in mediating enhanced post-prandial/fasting muscle growth [40, 60–62], thereby suggesting a stimulatory effect on Igf activity.…”