Wnt3alinks left-right determination with segmentation and anteroposterior axis elongation

Abstract

The alignment of the left-right (LR) body axis relative to the anteroposterior (AP) and dorsoventral (DV) axes is central to the organization of the vertebrate body plan and is controlled by the node/organizer. Somitogenesis plays a key role in embryo morphogenesis as a principal component of AP elongation. How morphogenesis is coupled to axis specification is not well understood. We demonstrate that Wnt3a is required for LR asymmetry. Wnt3a activates the Delta/Notch pathway to regulate perinodal expression of the left determinant Nodal, while simultaneously controlling the segmentation clock and the molecular oscillations of the Wnt/␤ ␤-catenin and Notch pathways. We provide evidence that Wnt3a, expressed in the primitive streak and dorsal posterior node, acts as a long-range signaling molecule, directly regulating target gene expression throughout the node and presomitic mesoderm. Wnt3a may also modulate the symmetrybreaking activity of mechanosensory cilia in the node. Thus, Wnt3a links the segmentation clock and AP axis elongation with key left-determining events, suggesting that Wnt3a is an integral component of the trunk organizer.

Transgenic Wnt/TCF pathway reporters: all you need is Lef?

“…The activity of TOPGAL was initially described in the context of developing hair follicles, where it partially overlaps with TCF gene expression patterns, correlates with nuclear b-catenin and is inducible by a misexpressed stabilized form of b-catenin Fuchs, 1999, Merrill et al, 2001;Jamora et al, 2003). The reporter is also active in the primitive streak and node of gastrulating embryos (Merrill et al, 2004;Nakaya et al, 2005), in developing lung epithelia (De Langhe et al, 2005;Shu et al, 2005) and during wound healing in skin (Fathke et al, 2006); in all cases, there is evidence for Wnt signaling in these tissues, if not in all TOPGAL-positive cells.…”

“…BAT-gal is expressed at many known sites of Wnt ligand expression in the embryo, as well as in intestinal adenomas in APC (Min/ þ ) mice, and responds to genetic manipulations of Wnt signaling in vivo (Maretto et al, 2003, Dessimoz et al, 2005Lie et al, 2005). A very similar (but independently built) mouse reporter, called BATlacZ, shows expression in the embryonic node and primitive streak that is partially lost in Wnt3a À/À embryos (Nakaya et al, 2005). In addition, two transgenic multimerized TCF reporters developed for Xenopus show expression in multiple known sites of embryonic Wnt signaling (Geng et al, 2003;Denayer et al, 2006).…”

Wnt Signaling in Mammalian Development: Lessons from Mouse Genetics

“…However, the primitive streak and its derivative, the tail bud, continue to produce mesoderm for another 5 days to form the paraxial presomitic mesoderm (PSM) and lateral plate mesoderm (LPM) that give rise to the trunk and tail. Analyses of Wnt reporters indicate that canonical Wnt signaling remains active in the primitive streak/tail bud, and this is due in part to Wnt3a, another canonical Wnt that starts to be expressed in the primitive streak from E7.5 (Nakaya et al 2005). Wnt3a -/-mutants fail to form posterior mesoderm and the tail bud but instead develop ectopic neural tissue, indicating that Wnt3a is required for the maintenance and the function of the primitive streak (Takada et al 1994;Yoshikawa et al 1997).…”

“…Wnt3a-induced Wnt signaling regulates the segmentation clock, at least in part, by activating Notch ligand Dll1 (Delta-like1) transcription in the PSM (Fig. 2) (Galceran et al 2004;Hofmann et al 2004;Nakaya et al 2005). Secondly, a gradient of Wnt signaling activity, likely established by the graded expression of Wnt3a along the A-P axis, is thought to constitute part of the "determination wavefront" that positions the segmentation boundary during somitogenesis (Pourquie 2011).…”

“…By manipulating Wnt activity gradient using b-catenin LOF and GOF mutants, studies show that high level Wnt activity maintains posterior PSM in an undifferentiated state permissive of Notch signaling oscillation, while a gradual reduction of Wnt activity in the anterior PSM sets the boundary to arrest Notch signaling oscillation and to activate genes required for segment formation (Aulehla et al 2008;Dunty et al 2008). Wnt3a is also required for left-right (L-R) axis determination because Wnt3a null mutants display laterality defects in multiple visceral organs (Nakaya et al 2005). In mice, L-R determination relies on Nodal expression at the periphery of the node, a specialized structure located immediately rostral to the primitive streak ( Fig.…”