Wnt signaling in vertebrate axis specification

Abstract

The Wnt pathway is a major embryonic signaling pathway that controls cell proliferation, cell fate, and body-axis determination in vertebrate embryos. Soon after egg fertilization, Wnt pathway components play a role in microtubule-dependent dorsoventral axis specification. Later in embryogenesis, another conserved function of the pathway is to specify the anteroposterior axis. The dual role of Wnt signaling in Xenopus and zebrafish embryos is regulated at different developmental stages by distinct sets of Wnt target genes. This review highlights recent progress in the discrimination of different signaling branches and the identification of specific pathway targets during vertebrate axial development.

Figure 1.

Conserved Wnt pathway branches and components. In the absence of Wnt signals, glycogen synthase kinase 3 (GSK3) binds Axin and APC to form the β-catenin destruction complex. Some Wnt proteins, such as Wnt8 and Wnt3a, stimulate Frizzled and LRP5/6 receptors to inhibit GSK3 activity and stabilize β-catenin (β-cat). Stabilized β-cat forms a complex with T-cell factors (e.g., TCF1/LEF1) to activate target genes. Moreover, GSK3 inhibition leads to target gene derepression by promoting TCF3 phosphorylation by homeodomain-interacting protein kinase 2 (HIPK2) through an unknown mechanism, for which β-catenin is required as a scaffold. This phosphorylation results in TCF3 removal from target promoters and gene activation. Other Wnt proteins, such as Wnt5a and Wnt11, use distinct receptors such as ROR2 and RYK, in addition to Frizzled, to control the the cytoskeletal organization through core planar cell polarity (PCP) proteins, small GTPases (Rho/Rac/Cdc42), and c-Jun amino-terminal kinase (JNK).

Figure 2.

Axis specification by early and late Wnt signaling involves distinct targets. After cortical rotation (black dotted arrow), early β-catenin accumulation in the dorsal equatorial region activates gene targets to generate the Spemann organizer. β-Catenin up-regulates several Wnt and bone morphogenetic protein (BMP) antagonists, including Dkk1, Cerberus, Shisa, Noggin, and Chordin. The pathway is inhibited by Wnt antagonists in the anterior tissues, but the zygotic activation of Wnt8 causes ventral and posterior accumulation of β-catenin during gastrulation. The target genes of this late Wnt signaling, including Cdx, Vent, Meis, Gbx, and Msx, are critical for the specification of ventroposterior mesodermal fates and lead to tail formation.

Figure 3.

Cross talk between Wnt, BMP, and FGF pathways during axis specification. (A) Sequential interaction of two pathways. FGF8a induces the expression of Wnt8 transcripts to promote neural crest formation in Xenopus neurulae. (B) Parallel interaction of two pathways at a target promoter (Vent2). Vent2 is up-regulated by BMP proteins acting through Smad1 interacting with the Smad binding site (SBS), whereas Wnt proteins act through TCF and the TCF-binding site (TBS). Both signals are responsible for the maximal activation of Vent2. (C) The cytoplasmic integration of two pathways. GSK3 phosphorylates the activated form of Smad1, marking it for degradation. Wnt proteins signal to inhibit or sequester GSK3, thereby promoting BMP target gene activation.