Wnt signaling in mammalian development: lessons from mouse genetics

Abstract

Wnts are evolutionarily conserved signaling ligands critical for animal development. Genetic engineering in the mouse has enabled investigators to acquire a detailed activation profile of the β-catenin-dependent canonical Wnt pathway during mouse development, and to manipulate Wnt pathway activities with great spatial and temporal precision. Together, these studies have not only revealed important functions of Wnt signaling at multiple stages of early mouse development, but also elucidated how the Wnt pathway interacts with other pathways to form signaling networks that confer the unique features of mammalian embryogenesis. Additionally, the planar cell polarity pathway has emerged as an essential β-catenin independent noncanonical Wnt pathway that coordinates cell polarity and regulates tissue morphogenesis in various mammalian developmental processes. Importantly, studies of Wnt signaling in mouse development have also revealed important pathogenic mechanisms of several congenital disorders in humans.

Figure 1.

Early mouse development and the role of Wnt3 in mammalian gastrulation. (A) Preimplantation blastocyst stage mouse embryo. (B) After implantation, the inner cell mass (ICM) expands into a radially symmetric cup of epithelium known as the epiblast that gives rise to the entire embryo proper. The polar trophectoderm, initially overlying the ICM, gives rise to the ectoplacental cone and the extraembryonic ectoderm (ExE) that do not contribute to the embryo proper, but form the placenta and trophoblast giant cells to support embryonic development. The ExE and epiblast is also covered by a layer of visceral endoderm (VE) derived from the primitive endoerm in the blastocyst. (C) Between E5.5 and 6.0, the distal VE undergo proximally oriented unidirectional movement, leading to the formation of the anterior VE (AVE) that marks the future anterior side of the embryo. The AVE inhibits Nodal signaling anteriorly to restrict Nodal-induced primitive streak formation in the posterior epiblast adjacent to the ExE. (D) During gastrulation, epiblast cells ingress through the primitive streak to give rise to the mesoderm and definitive endoderm. (E) Wnt3-induced canonical Wnt signaling is an integral part of a global signaling network that regulates gastrulation. Epiblast-derived Nodal activates the expression of Bmp4 in the neighboring ExE. Bmp4 signals back to activate Wnt3 expression in the epiblast. In turn, Wnt3 potentiates Nodal signaling by promoting the expression of Nodal and its coreceptor Cripto (important for Nodal auto-induction), thereby establishing the Nodal-Bmp4-Wnt3 positive feedback loop to sustain gastrulation. In addition, Wnt3 is also required for Fgf8 expression, which promotes ingressing epiblast cells to migrate out of the primitive streak during gastrulation.

Figure 2.

The role Wnt3a in early postgastrulation mouse development. A schematic diagram of the ventral view of an early postgastrulation (E8.0) mouse embryo showing that expression of Wnt3a in the primitive streak activates canonical Wnt signaling to maintain T (Brachyury) expression, thereby sustaining mesoderm production. Primitive streak-derived Wnt3a also signals to the adjacent paraxial presomatic mesoderm (PSM) to active Notch ligand Dll1 expression to regulate somitogenesis. Wnt3a-activated Dll1 expression in the PSM also regulates Nodal expression at the periphery of the node. Left-ward flow generated by rotating node cilia then enhances Nodal signaling and eventually, Nodal expression, on the left side of the node, leading to the L-R axis determination. Dll1, Delta 1; PSM, presomitic mesoderm; LSM, lateral plate mesoderm; S, somite; T, Brachyury.

Figure 3.

Wnt5a/Ror2 initiated PCP signaling regulates limb morphogenesis to promote limb skeletal formation. Wnt5a/Ror2-initiated PCP signaling regulates limb bud morphogenesis to control its shape and dimensions, which in turn ensure proper morphology of the prechondrogenic condensates in the limb and promote limb bud growth by maintaining cross-talk between spatially distinct signaling centers in the Fgf-Shh-Grem1 loop. AER: apical ectodermal ridge; Grem1: Gremlin 1; ZPA: zone of polarizing activity.