Wnt/planar cell polarity signaling controls morphogenetic movements of gastrulation and neural tube closure

Abstract

Gastrulation and neurulation are successive morphogenetic processes that play key roles in shaping the basic embryonic body plan. Importantly, they operate through common cellular and molecular mechanisms to set up the three spatially organized germ layers and to close the neural tube. During gastrulation and neurulation, convergent extension movements driven by cell intercalation and oriented cell division generate major forces to narrow the germ layers along the mediolateral axis and elongate the embryo in the anteroposterior direction. Apical constriction also makes an important contribution to promote the formation of the blastopore and the bending of the neural plate. Planar cell polarity proteins are major regulators of asymmetric cell behaviors and critically involved in a wide variety of developmental processes, from gastrulation and neurulation to organogenesis. Mutations of planar cell polarity genes can lead to general defects in the morphogenesis of different organs and the co-existence of distinct congenital diseases, such as spina bifida, hearing deficits, kidney diseases, and limb elongation defects. This review outlines our current understanding of non-canonical Wnt signaling, commonly known as Wnt/planar cell polarity signaling, in regulating morphogenetic movements of gastrulation and neural tube closure during development and disease. It also attempts to identify unanswered questions that deserve further investigations.

Keywords: Celsr1; Dishevelled; Frizzled; Morphogenesis; NTDs; Neural tube defects; PCP; Prickle; Vangl1; Vangl2; Wnt.

Fig. 1

Wnt/PCP signaling pathway and asymmetric distribution of “core” PCP protein complexes. A Wnt/PCP signaling is induced by non-canonical Wnt ligands binding to Fzd receptors and co-receptors such as Ror2, Ryk, glypican4/Knypek, and PTK7. Dvl-activated downstream effector proteins relay the signal to induce cytoskeletal rearrangements and/or transcription responses. The “core” PCP proteins form two separate complexes localized to opposite cell borders. The C-terminal cytoplasmic region of Vangl interacts with Prickle (Pk) and Scrib, which may contribute to the anterior localization of the Vangl-Prickle complex within a cell. Celsr protocadherins form homodimers between adjacent cells to propagate polarity information. Dvl family proteins function as important scaffolds in different Wnt signaling pathways. The N-terminal DIX (blue diamond) is involved in Wnt/ß-catenin signaling, while the central PDZ, the C-terminal DEP domains, and the extreme C-terminus PDZ domain-binding motif (PDB, purple triangle) regulate Wnt/PCP signaling. B Diagram shows the asymmetric subcellular localization of “core” PCP proteins within the epithelial plane

Fig. 2

Asymmetric cellular behaviors in morphogenetic movements during gastrulation and neurulation. A Mediolateral cell intercalation (“en face” view) drives CE movements to narrow and extend tissues along mediolateral and AP axes, respectively. B Radial cell intercalation (sagittal plane) reduces the number of cell layers and thins a multilayered epithelium into sheets or tubes. Extracellular matrix (ECM) deposition at the inner (basal) surface of the superficial layer can be also regulated by Wnt/PCP signaling and is involved in radial intercalation of multilayered deep cells. C Asymmetric cell division leads to differential partitions of signaling proteins and lineage segregation

Fig. 3

Neural plate formation and neural tube closure. Transverse sections in successive stages of neurulation show bending of the neural plate and convergence of the neural folds with presumptive neural crest approaching at the dorsal midline. Apical constriction generates wedge-shaped cells at the notochord (NC)-anchored medial hinge point (red) corresponding to the floor plate and at the dorsolateral hinge points (orange). These hinge points promote bending of the neural plate and convergence of the neural folds. It remains to be determined how PCP proteins regulate apical constrictions in different hinge points