eFGF, Xcad3 and Hox genes form a molecular pathway that establishes the anteroposterior axis in Xenopus

Abstract

Classical embryological experiments suggest that a posterior signal is required for patterning the developing anteroposterior axis. In this paper, we investigate a potential role for FGF signalling in this process. During normal development, embryonic fibroblast growth factor (eFGF) is expressed in the posterior of the Xenopus embryo. We have previously shown that overexpression of eFGF from the start of gastrulation results in a posteriorised phenotype of reduced head and enlarged proctodaeum. We have now determined the molecular basis of this phenotype and we propose a role for eFGF in normal anteroposterior patterning. In this study, we show that the overexpression of eFGF causes the up-regulation of a number of posteriorly expressed genes, and prominent among these are Xcad3, a caudal homologue, and the Hox genes, in particular HoxA7. There is both an increase of expression within the normal domains and an extension of expression towards the anterior. Application of eFGF-loaded beads to specific regions of gastrulae reveals that anterior truncations arise from an effect on the developing dorsal axis. Similar anterior truncations are caused by the dorsal overexpression of Xcad3 or HoxA7. This suggests that this aspect of the eFGF overexpression phenotype is caused by the ectopic activation of posterior genes in anterior regions. Further results using the dominant negative FGF receptor show that the normal expression of posterior Hox genes is dependent on FGF signalling and that this regulation is likely mediated by the activation of Xcad3. The biological activity of eFGF, together with its expression in the posterior of the embryo, make it a good candidate to fulfil the role of the ‘transforming’ activity proposed by Nieuwkoop in his ‘activation and transformation’ model for neural patterning.

Functional Roles of FGF Signaling in Early Development of Vertebrate Embryos

“…These results support the idea that FGF signaling is actively involved in posterior formation rather than in the anterior. Additional gain of function studies also in Xenopus drew similar conclusions; these were with overexpression of eFGF reported to induce a posteriorized phenotype with enlarging proctodeum and elevated expression level of posterior genes xcad3, hoxB9, and hoxA7 [125,171]. In these instances of upregulation of posterior genes, the anterior specific factors were suppressed and resulted in small or truncated head formation [125,171].…”

“…Both genes family of caudal homologs and Hox have been reported as the targets of FGF and Wnt signaling during AP elongation in vertebrates [125,171,[176][177][178]. However, a growing body of evidence indicate that FGF signaling is not a solo regulator of AP patterning.…”

“…However, a growing body of evidence indicate that FGF signaling is not a solo regulator of AP patterning. Indeed several signaling pathways (such as FGF, RA, and Wnt) actively participate, and coordinate action for overall embryonic axis formation in vertebrate embryos [125,171,176,177,[179][180][181][182]. One example is for MyoD, an important myogenic regulatory factor, which can be activated by efgf and wnt8 during the Xenopus embryonic development [183,184].…”

Retinoic Acid Signaling in Vertebrate Hindbrain Segmentation: Evolution and Diversification

“…In light of their ancient and fundamental roles in regulating morphogenesis and A-P patterning, the amplification and divergence of Hox complements in vertebrates is thought to be a driver in the emergence of new traits and evolutionary novelties by being integrated in gene regulatory networks underlying morphological diversity [2,62,77,78] Diverse molecular and cellular mechanisms are thought to contribute to the regulation and generation of collinear domains of Hox expression [20,21,[79][80][81][82][83][84][85][86]. Experimental studies in a wide range of vertebrates and invertebrates have revealed that collinear Hox expression arises in part through the ability of Hox clusters to integrate information from A-P signaling centers in response to cues from major signaling pathways, such as retinoic acid (RA), fibroblast growth factor (FGF), and Wnts [21,[87][88][89][90][91][92][93]. For example, in vertebrate model systems, opposing gradients of RA and FGFs have been shown to regulate nested domains of Hox expression in the CNS and in mesodermal domains that control specification of vertebral identities and axial elongation (Figure 1a,b) [91,[94][95][96][97][98][99].…”

The secreted serine protease xHtrA1 is a positive feedback regulator of long-range FGF signaling.

“…During early vertebrate development, FGF signaling is crucial for the induction of mesoderm and endoderm, neural fate specification, axial polarity and morphogenetic movements (Böttcher and Niehrs, 2005). Studies in Xenopus have first demonstrated a role of FGFs in the induction and migration of mesoderm during trunk and tail development (Slack et al, 1996). In chick and Xenopus embryos, FGFs participate in the induction of neural fate (Hongo et al, 1999;Streit et al, 2000;Wilson et al, 2000;Hardcastle et al, 2000;Pera et al, 2003, De Robertis and).…”