Posteriorization by FGF, Wnt, and Retinoic Acid Is Required for Neural Crest Induction

Abstract

The neural crest is a unique cell population induced at the lateral border of the neural plate. Neural crest is not produced at the anterior border of the neural plate, which is fated to become forebrain. Here, the roles of BMPs, FGFs, Wnts, and retinoic acid signaling in neural crest induction were analyzed by using an assay developed for investigating the posteriorization of the neural plate. Using specific markers for the anterior neural plate border and the neural crest, the posterior end of early neurula embryos was shown to be able to transform the anterior neural plate border into neural crest cells. In addition, tissue expressing anterior neural plate markers, induced by an intermediate level of BMP activity, was transformed into neural crest by posteriorizing signals. This transformation was mimicked by bFGF, Wnt-8, or retinoic acid treatment and was also inhibited by expression of the dominant negative forms of the FGF receptor, the retinoic acid receptor, and Wnt signaling molecules. The transformation of the anterior neural plate border into neural crest cells was also achieved in whole embryos, by retinoic acid treatment or by use of a constitutively active form of the retinoic acid receptor. By analyzing the expression of mesodermal markers and various graft experiments, the expression of the mutant retinoic acid receptor was shown to directly affect the ectoderm. We thereby propose a two-step model for neural crest induction. Initially, BMP levels intermediate to those required for neural plate and epidermal specification induce neural folds with an anterior character along the entire neural plate border. Subsequently, the most posterior region of this anterior neural plate border is transformed into the neural crest by the posteriorizing activity of FGFs, Wnts, and retinoic acid signals. We discuss a unifying model where lateralizing and posteriorizing signals are presented as two stages of the same inductive process required for neural crest induction.

Midkine‐b regulates cell specification at the neural plate border in zebrafish

“…Of interest, studies in Xenopus have shown that retinoid signaling is involved in early ncc induction (Villanueva et al, 2002). However, little is known about the role of RA during ncc development in zebrafish.…”

“…FGFs are thought to cooperate with Wnt/␤-catenin signaling during early induction of ncc formation (LaBonne and Bronner-Fraser, 1998;Villanueva et al, 2002). In zebrafish, gene knockdown studies demonstrated that wnt8 is required for initial ncc induction (Lewis et al, 2004).…”

“…Investigations in zebrafish show that in particular wnt8 is essential for ncc formation (Lewis et al, 2004). A third pathway thought to regulate ncc formation is activated by FGF, which is also essential for posteriorization the neural plate (LaBonne and Bronner-Fraser, 1998;Villanueva et al, 2002). Villanueva et al (2002) also investigated the role of retinoic acid (RA) signaling on ncc induction in Xenopus, but the significance of RA for zebrafish ncc formation remains unclear.…”

“…A third pathway thought to regulate ncc formation is activated by FGF, which is also essential for posteriorization the neural plate (LaBonne and Bronner-Fraser, 1998;Villanueva et al, 2002). Villanueva et al (2002) also investigated the role of retinoic acid (RA) signaling on ncc induction in Xenopus, but the significance of RA for zebrafish ncc formation remains unclear. Studies in zebrafish showed that also the Delta-Notch pathway is required for the correct establishment of ncc and the cell fate decision between ncc and Rohon-Beard (RB) sensory neuron formation at the neural plate border (Cornell and Eisen, 2000).…”

How to become neural crest: From segregation to delamination

“…It has been proposed that the origins of the rostrocaudal differences of the NCCs are established very early, at the open neural plate stage, as a result of posteriorizing signals arising from the posterior region of the embryo (Aybar and Mayor, 2002). Some of the signals involved could be Wnt and retinoic acid signals, which at least in Xenopus are responsible for a posteriorizing activity required for neural crest induction (Villanueva et al, 2002). However, apart from external signals, intrinsic properties determine the A-P identity of the crest cells and consequently their final destination.…”