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

Weidong Zhu, Ichiro Shiojima, Yuzuru Ito, Zhi Li, Hiroyuki Ikeda, Masashi Yoshida, Atsuhiko T. Naito, Jun-ichiro Nishi, Hiroo Ueno, Akihiro Umezawa, Tohru Minamino, Toshio Nagai, Akira Kikuchi, Makoto Asashima and Issei Komuro ()
Additional contact information
Weidong Zhu: Chiba University Graduate School of Medicine
Ichiro Shiojima: Chiba University Graduate School of Medicine
Yuzuru Ito: ICORP Organ Regeneration Project, Japan Science and Technology Agency (JST)
Zhi Li: Chiba University Graduate School of Medicine
Hiroyuki Ikeda: Chiba University Graduate School of Medicine
Masashi Yoshida: Chiba University Graduate School of Medicine
Atsuhiko T. Naito: Chiba University Graduate School of Medicine
Jun-ichiro Nishi: Chiba University Graduate School of Medicine
Hiroo Ueno: Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA
Akihiro Umezawa: National Institute for Child Health and Development
Tohru Minamino: Chiba University Graduate School of Medicine
Toshio Nagai: Chiba University Graduate School of Medicine
Akira Kikuchi: Graduate School of Biomedical Sciences, Hiroshima University
Makoto Asashima: ICORP Organ Regeneration Project, Japan Science and Technology Agency (JST)
Issei Komuro: Chiba University Graduate School of Medicine

Nature, 2008, vol. 454, issue 7202, 345-349

Abstract: IGF signalling and Wnt signalling linked in cardiogenmesis 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.

Date: 2008
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DOI: 10.1038/nature07027

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