Planar Cell Polarity Signaling: Coordinated Crosstalk for Cell Orientation

Abstract

The planar cell polarity (PCP) system is essential for positioning cells in 3D networks to establish the proper morphogenesis, structure, and function of organs during embryonic development. The PCP system uses inter- and intracellular feedback interactions between components of the core PCP, characterized by coordinated planar polarization and asymmetric distribution of cell populations inside the cells. PCP signaling connects the anterior-posterior to left-right embryonic plane polarity through the polarization of cilia in the Kupffer's vesicle/node in vertebrates. Experimental investigations on various genetic ablation-based models demonstrated the functions of PCP in planar polarization and associated genetic disorders. This review paper aims to provide a comprehensive overview of PCP signaling history, core components of the PCP signaling pathway, molecular mechanisms underlying PCP signaling, interactions with other signaling pathways, and the role of PCP in organ and embryonic development. Moreover, we will delve into the negative feedback regulation of PCP to maintain polarity, human genetic disorders associated with PCP defects, as well as challenges associated with PCP.

Keywords: Hippo signaling; Notch signaling; Wnt signaling; negative regulation; neural tube defects (NTDs); planar cell polarity (PCP); tissue morphogenesis.

Figure 1

PCP-mediated signaling pathway in Drosophila and mouse. Planar cell polarity (PCP) signaling in flies and mice is organized similarly. Orthologous genes (have similar colors) are shown. Observe the heterophilic interactions between the proteins fz/Fzd and vang/Vangl, and the homophilic interactions between the fmi/Celsr pair. While the mechanism of Drosophila frizzled activation is yet unknown, at least some of the ligands in vertebrates are known. Not every paralog of vertebrates has been linked to PCP signaling. Ankrd6, also known as Diversin, is Ankyrin repeat 6 and may be orthologous to Diego.

Figure 2

Cilial PCP signaling pathway. Fuzzy arbitrates the relative activity of canonical and noncanonical (PCP) Wnt pathways and transports Dvl to the cilium via Rab8(+) vesicular traffic. Rab8 and Dvl2 must be recruited by Fuzzy to the polarized trafficking route in ciliated cells for both molecules to reach the primary cilium. Dvl2, which is intracellularly accessible for canonical Wnt signaling, is reduced by sequestering it into vesicles. Dvl2 orchestrates basal body polarization and promotes PCP signaling at the cilium of wild-type cells. Without Fuzzy, ciliogenesis is hampered, Dvl2 recruitment to the basal bodies is impaired, and the Rab8-trafficking route is interfered with.

Figure 3

Asymmetric localization of PCP proteins promotes convergent extension motion in neuro-epithelium sheet.