Wnt signals provide a timing mechanism for the FGF-retinoid differentiation switch during vertebrate body axis extension

Abstract

Differentiation onset in the vertebrate body axis is controlled by a conserved switch from fibroblast growth factor (FGF) to retinoid signalling, which is also apparent in the extending limb and aberrant in many cancer cell lines. FGF protects tail-end stem zone cells from precocious differentiation by inhibiting retinoid synthesis, whereas later-produced retinoic acid (RA) attenuates FGF signalling and drives differentiation. The timing of RA production is therefore crucial for the preservation of stem zone cells and the continued extension of the body axis. Here we show that canonical Wnt signalling mediates the transition from FGF to retinoid signalling in the newly generated chick body axis. FGF promotes Wnt8c expression, which persists in the neuroepithelium as FGF signalling declines. Wnt signals then act here to repress neuronal differentiation. Furthermore, although FGF inhibition of neuronal differentiation involves repression of the RA-responsive gene, retinoic acid receptor ␤ (RAR␤), Wnt signals are weaker repressors of neuron production and do not interfere with RA signal transduction. Strikingly, as FGF signals decline in the extending axis, Wnt signals now elicit RA synthesis in neighbouring presomitic mesoderm. This study identifies a directional signalling relay that leads from FGF to retinoid signalling and demonstrates that Wnt signals serve, as cells leave the stem zone, to permit and promote RA activity, providing a mechanism to control the timing of the FGF-RA differentiation switch.

Cell-autonomous integrin control of Wnt and Notch signalling during somitogenesis

“…2I) or dickkopf 1 (Dkk1; not shown)] (Glinka et al, 1998;Peters et al, 1999), or by treating embryos with LiCl, which renders Wnt signalling constitutive. These respective treatments inhibit and enhance transcription of Lef1, a Wnt target gene, in the anterior PSM (Gibb et al, 2009;Olivera-Martinez and Storey, 2007) (Fig. 2I; Fig.…”

“…Levels of -catenin are higher (Aulehla et al, 2008), although levels in the anterior must still be sufficient to support the anterior expression of Lef1 (Gibb et al, 2009;Olivera-Martinez and Storey, 2007) and Ripply2 (Biris et al, 2007). Genetic regulatory interactions also differ between the two domains (Morales et al, 2002;Morimoto et al, 2005), presumably due in part to combinatorial interactions between signalling pathways and regionalised accessory factors that together determine regionally restricted outcomes such as the Wnt responsiveness of Lef1 transcription (Fig.…”

Fate of retinoic acid–activated embryonic cell lineages

“…and to maintain a tight bilateral symmetry in somitogenesis (Diez del Corral et al, 2003;Diez del Corral and Storey, 2004;Vermot and Pourquie, 2005;Sirbu and Duester, 2006;Olivera-Martinez and Storey, 2007). According to the expression patterns of the synthesizing enzyme Raldh2 and of the RAREhsp68-lacZ transgene (Diez del Corral et al, 2003;Sirbu and Duester, 2006;Vilhais-Neto et al, 2010), RA activity was shown to be strong in somitic and rostral presomitic mesoderm (PSM), and to fade posteriorly in the prospective somite-forming region.…”

Retinoic acid signaling in development: Tissue‐specific functions and evolutionary origins

“…In general, RA signaling inhibits the signals from the caudal source of FGF8 hence triggering somite formation by activation of segmentation genes (Moreno and Kintner, 2004). Recent studies have also proposed Wnt signaling as a key player in reciprocal inhibition of RA and FGF: in chicken, wnt8c expression in the transition zone is activated by FGF8 emanating from the posterior stem zone with WNT8C in turn activating expression of raldh2 at more anterior levels of the AP (Olivera-Martinez and Storey, 2007).…”