Multifunctional Cyr61 Modulates Gastrulation

Abstract

Latinkic et al. investigated the role of Cyr61 on early development in Xenopus and discovered that it was required for cell movement during gastrulation, an effect that depended on both cell adhesion and modulation of the Wnt signaling pathway. During gastrulation, cells change their shapes, migrate, and receive fate determination signals. Cyr61, a secreted, heparin-binding, extracellular matrix-associated protein, is a member of a protein family characterized by four domains, each of which is defined by similarities to domains found in other proteins. Latinkic et al. demonstrated that both Cyr61 overexpression (through RNA or protein injection) and depletion (through injection of antisense morpholino oligonucleotides) disrupted cell movement during gastrulation. Morpholino experiments on dissociated cells indicated that the ability to form Ca 2+ -dependent contacts was impaired. The authors grew activin-treated cells on surfaces coated with various substrata, including Cyr61 and a Cyr61 mutant lacking the C-terminal (CT) domain, and demonstrated that this domain was required for Cyr61-mediated cell adhesion. Cyr61 could stimulate the formation of secondary axes, an effect that can be mediated through Wnt activation. Consistent with this, Cyr61 activated a gene reporter responsive to Wnt-β-catenin signaling pathways; the authors used Cyr61 deletion mutants to show that this depended on a different domain, the insulin-like growth factor-binding protein domain. Unexpectedly, Cyr61 inhibited Wnt-mediated secondary axis formation and reporter gene activation. Unlike Wnt pathway activation, Wnt pathway inhibition depended on the CT domain. Thus, Cyr61 appears to regulate gastrulation both through effects on cell adhesion and through activation or inhibition of Wnt signaling mediated through distinct protein domains. B. V. Latinkic, S. Mercurio, B. Bennett, E. M. A. Hirst, Q. Xu, L. F. Lau, T. J. Mohun, J. C. Smith, Xenopus Cyr61 regulates gastrulation movements and modulates Wnt signalling. Development 130 , 2429-2441 (2003). [Abstract] [Full Text]