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Nature 2008 Jul 17;4547202:345-9. doi: 10.1038/nature07027.
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IGFBP-4 is an inhibitor of canonical Wnt signalling required for cardiogenesis.

Zhu W , Shiojima I , Ito Y , Li Z , Ikeda H , Yoshida M , Naito AT , Nishi J , Ueno H , Umezawa A , Minamino T , Nagai T , Kikuchi A , Asashima M , Komuro I .

Insulin-like growth-factor-binding proteins (IGFBPs) bind to and modulate the actions of insulin-like growth factors (IGFs). 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 unknown. 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.

PubMed ID: 18528331
Article link: Nature

Species referenced: Xenopus laevis
Genes referenced: gata4 hhex igfbp1 igfbp2 igfbp4 igfbp5 il17f ins lrp6 mhc1a myc myh6 nkx2-5 nodal3.1 sia1 tnni3 wnt3a
Morpholinos: Igfbp4 MO1 Igfbp4 MO2

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