IGFBP-4 is an inhibitor of canonical Wnt signalling required for cardiogenesis

Insulin-like growth-factor-binding proteins (IGFBPs) modulate the actions of insulin-like growth factors (IGFs) but they also have functions independent of IGFs. This study reports a new function for IGFBP-4 as a cardiogenic growth factor, showing that IGFBP-4 enhances cardiomyocyte differentiation in vitro, and knockdown of IGFBP-4 attenuated cardiomyogenesis both in vitro and in vivo. The effect was independent of IGF binding, and was mediated by canonical Wnt signalling. IGFBP-4 physically interacted with a Wnt receptor Frizzled 8 (Frz8) and a Wnt co-receptor low-density lipoprotein receptor-related protein 6 (LRP6), and inhibited Wnt3A binding to Frz8 and LRP6. This paper provides the first molecular link between IGF signalling and Wnt signalling. The research could thus pave the way towards understanding how anomalies in this process give rise to congenital heart defects and could potentially yield new strategies to repair tissue damaged by heart attacks. This study reports a function for IGFBP-4 as a cardiogenic growth factor, showing that IGFBP-4 enhances cardiomyocyte differentiation in vitro, and knockdown of IGFBP-4 attenuated cardiomyogenesis both in vitro and in vivo. The effect was independent of IGF binding, and was mediated by canonical Wnt signalling. IGFBP-4 physically interacted with a Wnt receptor Frizzled 8 (Frz8) and a Wnt co-receptor low-density lipoprotein receptor-related protein 6 (LRP6), and inhibited Wnt3A binding to Frz8 and LRP6. Insulin-like growth-factor-binding proteins (IGFBPs) bind to and modulate the actions of insulin-like growth factors (IGFs)1. Although some of the actions of IGFBPs have been reported to be independent of IGFs, the precise mechanisms of IGF-independent actions of IGFBPs are largely unknown1,2. Here we report a previously unknown function for IGFBP-4 as a cardiogenic growth factor. IGFBP-4 enhanced cardiomyocyte differentiation in vitro, and knockdown of Igfbp4 attenuated cardiomyogenesis both in vitro and in vivo. The cardiogenic effect of IGFBP-4 was independent of its IGF-binding activity but was mediated by the inhibitory effect on canonical Wnt signalling. IGFBP-4 physically interacted with a Wnt receptor, Frizzled 8 (Frz8), and a Wnt co-receptor, low-density lipoprotein receptor-related protein 6 (LRP6), and inhibited the binding of Wnt3A to Frz8 and LRP6. Although IGF-independent, the cardiogenic effect of IGFBP-4 was attenuated by IGFs through IGFBP-4 sequestration. IGFBP-4 is therefore an inhibitor of the canonical Wnt signalling required for cardiogenesis and provides a molecular link between IGF signalling and Wnt signalling.