The involvement of PCP proteins in radial cell intercalations during Xenopus embryonic development

Abstract

The planar cell polarity (PCP) pathway orients cells in diverse epithelial tissues in Drosophila and vertebrate embryos and has been implicated in many human congenital defects and diseases, such as ciliopathies, polycystic kidney disease and malignant cancers. During vertebrate gastrulation and neurulation, PCP signaling is required for convergent extension movements, which are primarily driven by mediolateral cell intercalations, whereas the role for PCP signaling in radial cell intercalations has been unclear. In this study, we examine the function of the core PCP proteins Vangl2, Prickle3 (Pk3) and Disheveled in the ectodermal cells, which undergo radial intercalations during Xenopus gastrulation and neurulation. In the epidermis, multiciliated cell (MCC) progenitors originate in the inner layer, but subsequently migrate to the embryo surface during neurulation. We find that the Vangl2/Pk protein complexes are enriched at the apical domain of intercalating MCCs and are essential for the MCC intercalatory behavior. Addressing the underlying mechanism, we identified KIF13B, as a motor protein that binds Disheveled. KIF13B is required for MCC intercalation and acts synergistically with Vangl2 and Disheveled, indicating that it may mediate microtubule-dependent trafficking of PCP proteins necessary for cell shape regulation. In the neural plate, the Vangl2/Pk complexes were also concentrated near the outermost surface of deep layer cells, suggesting a general role for PCP in radial intercalation. Consistent with this hypothesis, the ectodermal tissues deficient in Vangl2 or Disheveled functions contained more cell layers than normal tissues. We propose that PCP signaling is essential for both mediolateral and radial cell intercalations during vertebrate morphogenesis. These expanded roles underscore the significance of vertebrate PCP proteins as factors contributing to a number of diseases, including neural tube defects, tumor metastases, and various genetic syndromes characterized by abnormal migratory cell behaviors.

Using Xenopus to understand human disease and developmental disorders

“…Xenopus also has greatly enhanced our understanding of DNA replication and repair (Kalb, Mallery, Larkin, Huang, & Hiom, ; Long, Joukov, Budzowska, & Walter, ; Räschle et al, ; Shintomi, Takahashi, & Hirano, ; Zhang et al, ), and the mechanisms of genome organization, transcriptional regulation, and epigenetics (Belikov, Berg, & Wrange, ; Bogdanović et al, ; Buisine et al, ; Gazdag, Jacobi, van Kruijsbergen, Weeks, & Veenstra, ; Gao et al, ; Hontelez et al, ; Owens et al, ; Tamaoki et al, ; Wang et al, ; Wen, Fu, Guo, Chen, & Shi, ). Numerous studies in Xenopus elucidate mechanisms of morphogenesis and organogenesis ( Agricola et al, ; Bestman, Huang, Lee‐Osbourne, Cheung, & Cline, ; Metikala, Neuhaus, & Hollemann, ; Mimoto, Kwon, Green, Goldman, & Christian, ; Nie & Bronner, ; Okada, Wen, Miller, Su, & Shi, ; Ossipova et al, ; Tanizaki, Ishida‐Iwata, Obuchi‐Shimoji, & Kato, ). Many of the components of the well‐known signaling pathways were discovered in Xenopus and fly, and new discoveries in this field continue to rely on Xenopus (e.g., Lee et al, ; Lee, Shi, & Zheng, ; Park et al, ; Zhang et al, ; Zhao, Shi, Winey, & Klymkowsky, ).…”

Planar cell polarity in moving cells: think globally, act locally

“…In zebrafish and mice, polarized radial intercalations of mesodermal cells (cells moving from a deeper layer into a more superficial layer) also contribute to axial extension and depend on PCP signaling (Yen et al, 2009;Yin et al, 2008), but it is currently unknown how PCP proteins polarize this type of neighbor exchange during mesodermal CE. Recent work in Xenopus, in which epidermal cells undergo PCP-dependent radial intercalation, has suggested that Vangl-Pk complexes at the tips of intercalating cells drive invasion into the overlying cell layer (Ossipova et al, 2015a). In this case, the role of Vangl2-Pk is presumably to regulate protrusive activity, which is different from the role of PCP signaling at non-protrusive surfaces during CE.…”

Vangl2 coordinates cell rearrangements during gut elongation

“…For example, Prickle1 synergizes with Vangl2 in establishing or maintaining the apicobasal polarity of epiblast cells of the early mouse embryo . Likewise, cells of both the Xenopus neuroectoderm and skin have an apical enrichment of Vangl2 required to undergo radial intercalation to a more superficial position within their respective tissue; Vangl2 is found at the tips of these intercalating cells to drive their invasion into the overlying cell layer …”