The IGF Pathway Regulates Head Formation by Inhibiting Wnt Signaling in Xenopus

Abstract

The insulin-like growth factors (IGFs) are well known mitogens, both in vivo and in vitro, while functions in cellular differentiation have also been indicated. Here, we demonstrate a new role for the IGF pathway in regulating head formation in Xenopus embryos. Both IGF-1 and IGF-2, along with their receptor IGF-1R, are expressed early during embryogenesis, and the IGF-1R is present particularly in anterior and dorsal structures. Overexpression of IGF-1 leads to anterior expansion of head neural tissue as well as formation of ectopic eyes and cement gland, while IGF-1 receptor depletion using antisense morpholino oligonucleotides drastically reduces head structures. Furthermore, we demonstrate that IGF signaling exerts this effect by antagonizing the activity of the Wnt signal transduction pathway in the early embryo, at the level of beta-catenin. Thus, the IGF pathway is required for head formation during embryogenesis.

Insulin-like growth factor signaling regulates zebrafish embryonic growth and development by promoting cell survival and cell cycle progression

“…13,14 Several studies in Xenopus, however, suggested that IGF1R signaling induces the formation of anterior neural tissue, the cellular basis for which was change in cell fate. 15,16 A similar study in zebrafish was also reported. 17 Thus, there is a major discrepancy concerning the cellular basis for the conserved IGF1R signaling cascade during vertebrate development.…”

“…These phenotypes are consistent with those reported in mutant mice 11,12,23 and Drosophila 24 but differ from previous studies in Xenopus. 15,16 Although IGF signaling was proposed to be an anteriorizing or neural induction signal in Xenopus, 15,16 our results show that reduction of Igf signaling not only affects retina, but also other tissues throughout the zebrafish embryo. This is most evident in disrupted CaP motoneuron survival and increased apoptosis in the spinal cord.…”

“…Given recent reports for a role for IGF signaling in the induction of anterior neural tissue and patterning [15][16][17] , we tested whether igf1r MOs and dnIGF1R: GFP mRNA-injected embryos exhibited defects in patterning the central nervous system (CNS). Neither igf1r MOs nor dnIGF1R:GFP mRNA-injected embryos exhibited defects in CNS patterning, as indicated by the expression of otx2 (presumptive forebrain and midbrain), pax6b (eye field and forebrain) and shh (notochord) at 10 hpf.…”

“…Both methods were shown to reduce IGF1R signaling in vivo effectively and they yielded similar phenotypes. The study by Richard-Parpaillon et al 16 used only one igf1r MO targeting one Xenopus igf1r gene. Pera et al 15 and Eivers et al 17 overexpressed a secreted form of a truncated IGF1R lacking both the transmembrane and intracellular domains.…”

Xeya3 regulates survival and proliferation of neural progenitor cells within the anterior neural plate of Xenopus embryos

“…It is reasonable that an EYA3-specific cofactor or a specific mix of cofactors exists in the anterior neuroectoderm, because we found that the hyperplasia of the brain upon Xeya3 overexpression was strictly limited to this area. In Xenopus, hyperplasia of the forebrain region was also observed upon the activation of the insulin-like growth factor or upon repression of canonical Wnt signalling pathways, respectively, and by overexpression of either Six3 or Six6 (Zuber et al, 1999;Bernier et al, 2000;Pera et al, 2001;Richard-Parpaillon et al, 2002;Lagutin et al, 2003). However, in all these cases, the increase of forebrain tissue was explained by a transdifferentiation/determination of non-neural tissue, which was not observed upon Xeya3 overexpression.…”