Planar cell polarity (PCP), initially studied in the retina and the wing of insects Oncopeltus fasciatus and Drosophila melanogaster (Lawrence and Shelton, 1975; Gubb and García-Bellido, 1982), refers to coordinated cellular orientation within the plane of an epithelium or a tissue. This fascinating process exerts wide functions in organizing the asymmetric cellular choreography and the spatially oriented pattern during tissue and organ morphogenesis, contributing to, for example, the architectural beauty of the Drosophila compound eye and the mammalian cochlea. The phenomenon of PCP is mostly regulated by a set of evolutionarily conserved proteins, including Frizzled receptors, Flamingo (Celsr1-3 in vertebrates), Dishevelled (Dvl1-3 in vertebrates), Diego (Ankrd6 in vertebrates), Van Gogh (Vangl1-2 in vertebrates), and Prickle (Prickle1-3 in vertebrates). These “core” PCP proteins transduce Wnt/PCP signaling to regulate cytoskeletal rearrangements and polarized cell behaviors in a variety of morphogenetic processes (Wallingford, 2012; Yang and Mlodzik, 2015; Henderson et al., 2018). Increasing evidence suggests that several vertebrate Wnts, such as Wnt5a and Wnt11, are also important components of the Wnt/PCP pathway, although they are not considered as “core” PCP proteins.

There are also other conserved protein complexes that function as important PCP regulators in Drosophila and vertebrates. The heteromeric protocadherins Fat4 and dachsous cadherin-related 1 (Dchs1) represent the second PCP pathway (Fat/Dchs module) that is regulated by the Golgi resident transmembrane kinase Four-jointed or Fj (Blair and McNeill, 2018). The Scrib (Scrb1 or Scribble1) polarity complex, originally identified as a regulator of apico-basal cell polarity, consists of Scrib, Discs-large (Dlg) and Lethal-giant larvae (Lgl) proteins (Milgrom-Hoffman and Humbert, 2018). These pathways exert broad activity in cellular signaling and cytoskeletal organization. They function in concert with or independently of the “core” Wnt/PCP pathway to regulate cell polarity. Two additional systems, the Fat2/Lar (leukocyte antigen-related receptor tyrosine phosphatase) and Toll-8/Cirl (adhesion G protein-coupled receptor) pathways, have been recently shown to instruct some Drosophila PCP processes, but their functions in vertebrates merit future investigation (Lavalou and Lecuit, 2022).

The “core” PCP pathway, the Fat/Dchs polarity module and the Scrib complex are critically involved in tissue and organ morphogenesis, from the emergence of organ primordia to terminal organogenesis and tissue homeostasis. In vertebrates, the functions of PCP proteins (herein collectively referred to as regulators of PCP-dependent cell behaviors) have been well documented in many morphogenetic processes, such as neural tube closure, embryonic left-right symmetry breaking, heart and gut morphogenesis, lung and kidney branching, orientation of inner ear hair cells, and proximal-distal limb bud elongation (Yang and Mlodzik, 2015; Henderson et al., 2018). Mutations of PCP genes impair organ development and are closely linked to various congenital anomalies, including neural tube defects (Wang et al., 2019), laterality disorders (Grimes and Burdine, 2017), hearing deficits (May-Simera and Kelley, 2012), lung and kidney diseases (Vladar and Königshoff, 2020; Torban and Sokol, 2021), as well as limb abnormalities (Gao and Yang, 2013). Importantly, PCP proteins regulate common cellular processes underlying the outgrowth and elongation of tissue primordia, such as convergent extension (CE) movements driven by oriented cell division and intercalation (Wallingford, 2012). Therefore, their dysfunctions can lead to multiple phenotypes, highlighting a general importance in organogenesis. There are many excellent reviews focusing on PCP functions in specific aspects of morphogenesis, but a more comprehensive analysis of PCP regulators during development of different organs that display PCP-dependent cellular organization is beneficial for understanding their complex interplay in the establishment of cell polarity. This review attempts to present past achievements and latest advances of PCP protein functions in asymmetric organogenesis, with the aim to identify challenges in deciphering the extraordinary process of asymmetry formation.