Motile cilia in ependymal cells, which line the cerebral ventricles, exhibit a coordinated beating motion that drives directional cerebrospinal fluid (CSF) flow and guides neuroblast migration. At the apical cortex of these multi-ciliated cells, asymmetric localization of planar cell polarity (PCP) proteins is required for the planar polarization of microtubule dynamics, which coordinates cilia orientation. Daple is a disheveled-associating protein that controls the non-canonical Wnt signaling pathway and cell motility. Here, we show that Daple-deficient mice present hydrocephalus and their ependymal cilia lack coordinated orientation. Daple regulates microtubule dynamics at the anterior side of ependymal cells, which in turn orients the cilial basal bodies required for the directional cerebrospinal fluid flow. These results demonstrate an important role for Daple in planar polarity in motile cilia and provide a framework for understanding the mechanisms and functions of planar polarization in the ependymal cells.
In gastric cancer, the non-canonical Wnt signaling pathway is activated by Wnt5a, which has a critical role in disease outcome. Previous studies have shown that Wnt5a mediates the expression of the extracellular matrix protein laminin c2 through Rac and JNK activation to promote gastric cancer progression. However, the mechanism of this regulatory pathway has not been completely addressed. The scaffold protein Dvl is a major component of the Wnt signaling pathway. Here, we show that Dvl-associating protein with a high frequency of leucine residues (Daple) mediates Wnt5a-induced laminin c2 expression. Immunohistochemical analysis showed marked expression of Daple in advanced clinical stages of gastric cancer, where it highly correlated with Wnt5a ⁄ b and laminin c2 expression, the depth of wall invasion, and the frequency of lymph node metastasis. In cultured cancer cells, Daple depletion led to the suppression of Wnt5a-induced Rac and JNK activation, laminin c2 expression, and cell migration and invasion. Accordingly, Daple depletion also suppressed liver metastasis in a mouse xenograft model of gastric cancer. These results suggest that the non-canonical Wnt signaling pathway contributes to gastric cancer progression at least in part via Daple, which provides a new therapeutic opportunity for the treatment of the disease. Significant progress has been made in the diagnosis and treatment of gastric cancer, leading to a decrease in the mortality rate of patients with the disease. Nonetheless, many cases with delayed diagnosis and metastasis are intractable, making gastric cancer the third leading cause of cancer deaths worldwide.(1) To date, multiple genes, proteins and signaling pathways have been found to be deregulated in gastric cancer.(2-5) However, the mechanisms underlying the tumorigenesis, heterogeneity and metastasis of gastric cancer are less well understood.Previous studies have demonstrated that Wnt signaling represents one of the deregulated pathways in gastric cancer.(6) Wnt signaling is essential for embryonic development and adult tissue homeostasis and is involved in cancer initiation and progression. It consists of two distinct branches that signal intracellularly: canonical and non-canonical pathways.(7-9) Activation of the canonical pathway induces b-catenin nuclear accumulation and Wnt target gene transcription.(10) Mutations in components of the canonical pathway, such as b-catenin, adenomatous polyposis coli and Axin genes, are involved in human cancer initiation. (11,12) The non-canonical pathway is independent of b-catenin; instead, members of the Rho family of small GTPases, including Rac and Rho, and JNK transmit the signals to promote cell motility. (13,14) Accordingly, aberrant activation of non-canonical pathway components has been implicated as well in invasion and metastasis in human malignancies. (15) High levels of Wnt5a, a ligand that utilizes the non-canonical pathway, have been reported to promote invasion in advanced gastric cancer. (16)(17)(18) Wnt5a has been shown to induc...
Despite common consensus about the importance of planar cell polarity (PCP) proteins in tissue orientation, little is known about the mechanisms used by PCP proteins to promote planar polarization of cytoskeletons within individual cells. One PCP protein Fzd6 asymmetrically localizes to the apical cell membrane of multi-ciliated ependymal cells lining the lateral ventricular (LV) wall on the side that contacts cerebrospinal fluid flow. Individual ependymal cells have planar polarized microtubules that connect ciliary basal bodies (BBs) with the cell cortex of the Fzd side to coordinate cilia orientation. Here, we report that cytoplasmic dynein is anchored to the cell cortex of the Fzd side via an adapter protein Daple that regulates microtubule dynamics. Asymmetric localization of cortical dynein generates a pulling force on dynamic microtubules connected to BBs, which in turn orients BBs toward the Fzd side. This is required for coordinated cilia orientation on the LV wall.
Wounds in embryos heal rapidly through contraction of the wound edges. Despite well-recognized significance of the actomyosin purse string for wound closure, roles for other cytoskeletal components are largely unknown. Here, we report that the septin cytoskeleton cooperates with actomyosin and microtubules to coordinate circumferential contraction of the wound margin and concentric elongation of wound-proximal cells in embryos. Microtubules reoriented radially, forming bundles along lateral cell cortices in elongating wound-proximal cells. Depletion of septin 7 (Sept7) slowed wound closure by attenuating the wound edge contraction and cell elongation. ROCK/Rho-kinase inhibitor-mediated suppression of actomyosin contractility enhanced the Sept7 phenotype, whereas the Sept7 depletion did not affect the accumulation of actomyosin at the wound edge. The cortical microtubule bundles were reduced in wound-proximal cells in Sept7 knockdown (Sept7-KD) embryos, but forced bundling of microtubules mediated by the microtubule-stabilizing protein Map7 did not rescue the Sept7-KD phenotype. Nocodazole-mediated microtubule depolymerization enhanced the Sept7-KD phenotype, suggesting that Sept7 is required for microtubule reorganization during cell elongation. Our findings indicate that septins are required for the rapid wound closure by facilitating cortical microtubule reorganization and the concentric elongation of surrounding cells.
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