IGF binding proteins: Make another little piece of my heart now, baby

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Insulin-like growth-factor-binding protein 4 (IGFBP-4) promotes cardiac development by binding to Wnt co-receptors and inhibiting canonical Wnt signaling.

Insulin-like growth-factor-binding proteins (IGFBPs) regulate IGF signaling. IGFBPs also possess IGF-independent activities, but their function in this capacity is not yet well understood. In Nature, Komuro and colleagues now report that IGFBP-4 binds and inhibits components of the canonical Wnt signaling pathway to promote cardiomyocyte differentiation.

IGFBP-4 was identified in a screen to uncover soluble compounds that induced cardiomyocyte differentiation. Exogenous IGFBP-4 induced differentiation, whereas siRNA-mediated knockdown of IGFBP-4 blocked differentiation. This effect was independent of IGF-I and IGF-II, as an IGFBP-4 mutant unable to bind IGF was still able to promote differentiation.

Canonical Wnt signaling is necessary for cardiomyocyte differentiation; therefore, a potential role for IGFBP-4 in modulating Wnt signaling was evaluated. Immunoprecipitation analyses revealed that the carboxy-terminal region of IGFBP-4 bound to the extracellular domain of the Wnt co-receptors Lrp6 (low-density lipoprotein receptor-related protein 6) and Frz8 (Frizzled 8). Furthermore, IGFBP-4 competitively inhibited Wnt3a binding to Frz8 and blocked Frz8/Lrp6–Wnt3a–β-catenin-induced transcription. These results suggest that IGFBP-4 promotes differentiation by blocking Wnt-mediated Frz8/Lrp6 signaling.

The effect of IGFBP-4 on canonical Wnt signaling in vivo was evaluated in developing Xenopus embryos. IGFBP-4 expression was detected in the liver, suggesting that IGFBP-4 may regulate cardiomyocyte differentiation via paracrine signaling. Morpholino oligo (MO)-mediated knockdown of Xenopus IGFBP-4 (XIGFBP-4) blocked formation of the heart, which was rescued by expression of MO-resistant XIGFBP4 or dominant negative LRP6. Furthermore, injection of Lrp6 or Xwnt8 mRNA caused formation of a secondary developmental axis, which was blocked by co-injection of XIGFBP4. These results indicate that IGFBP-4 antagonizes canonical Wnt signaling downstream of LRP6 in vivo.

It is interesting to note that IGFBP-4 is expressed in liver tissue adjacent to the heart and is also detected in the cells that surround cardiomyocytes, but not in cardiomyocytes themselves. A previous study indicated that FGFs secreted by cardiac tissue induce liver development, and these data provide evidence for reciprocal paracrine signaling between the heart and liver. In addition, the IGFBP-1, 2 and 6 proteins can also bind LRP6 and Frz8. As their expression is low in cardiac tissue, it will be important to determine if the IGFBP–LRP/Fzd interaction regulates Wnt signal transduction in other developmental settings.

Emily J. Chenette
Signaling Gateway

Reference

Zhu, W. et al. IGFBP-4 is an inhibitor of canonical Wnt signalling required for cardiogenesis. Nature 454, 345-349 (2008) | Article | PubMed |