Polarized epithelial cells assemble a primary cilium by an unknown mechanism. After cytokinesis, the central part of the intercellular bridge, which is referred to as the midbody, is inherited as a remnant by one of the daughter cells. Here, Bernabé-Rubio et al. show that the midbody remnant meets the centrosome at the cell apex, enabling primary ciliogenesis.
Primary cilia are solitary, microtubule-based protrusions of the cell surface that play fundamental roles as photosensors, mechanosensors and biochemical sensors. Primary cilia dysfunction results in a long list of developmental and degenerative disorders that combine to give rise to a large spectrum of human diseases affecting almost any major body organ. Depending on the cell type, primary ciliogenesis is initiated intracellularly, as in fibroblasts, or at the cell surface, as in renal polarized epithelial cells. In this review, we have focused on the routes of primary ciliogenesis placing particular emphasis on the recently described pathway in renal polarized epithelial cells by which the midbody remnant resulting from a previous cell division event enables the centrosome for initiation of primary cilium assembly. The protein machinery implicated in primary cilium formation in epithelial cells, including the machinery best known for its involvement in establishing cell polarity and polarized membrane trafficking, is also discussed.
Lipid liquid–liquid immiscibility and its consequent lateral heterogeneity have been observed under thermodynamic equilibrium in model and native membranes. However, cholesterol‐rich membrane domains, sometimes referred to as lipid rafts, are difficult to observe spatiotemporally in live cells. Despite their importance in many biological processes, robust evidence for their existence remains elusive. This is mainly due to the difficulty in simultaneously determining their chemical composition and physicochemical nature, whilst spatiotemporally resolving their nanodomain lifetime and molecular dynamics. In this study, a bespoke method based on super‐resolution stimulated emission depletion (STED) microscopy and raster imaging correlation spectroscopy (RICS) is used to overcome this issue. This methodology, laser interleaved confocal RICS and STED‐RICS (LICSR), enables simultaneous tracking of lipid lateral packing and dynamics at the nanoscale. Previous work indicated that, in polarized epithelial cells, the midbody remnant licenses primary cilium formation through an unidentified mechanism. LICSR shows that lipid immiscibility and its adaptive collective nanoscale self‐assembly are crucial for the midbody remnant to supply condensed membranes to the centrosome for the biogenesis of the ciliary membrane. Hence, this work poses a breakthrough in the field of lipid biology by providing compelling evidence of a functional role for liquid ordered‐like membranes in primary ciliogenesis.
Myeloid-associated differentiation marker (MYADM) protein belongs to the MAL family and regulates raft domains in epithelial cells. Membrane rafts participate in inflammatory responses. This study shows that MYADM is expressed in endothelial cells and controls the endothelial barrier by regulating ICAM-1 expression through ezrin, radixin, and moesin proteins, connectors between plasma membrane domains and actin cytoskeleton.
Formins promote actin nucleation but also influence the microtubule cytoskeleton. Fernández-Barrera et al. show that formins activate the MRTF-SRF transcriptional complex to induce expression of the α-TAT1 gene encoding the enzyme responsible for tubulin acetylation, thus revealing a mechanism underpinning the relationship between formins and tubulin acetylation.
The primary cilium is a single non-motile protrusion of the plasma membrane of most types of mammalian cell. The structure, length and function of the primary cilium must be tightly controlled because their dysfunction is associated with disease. Caveolin 1 (Cav1), which is best known as a component of membrane invaginations called caveolae, is also present in non-caveolar membrane domains whose function is beginning to be understood. We show that silencing of α and β Cav1 isoforms in different cell lines increases ciliary length regardless of the route of primary ciliogenesis. The sole expression of Cav1α, which is distributed at the apical membrane, restores normal cilium size in Cav1 KO MDCK cells. Cells KO for only Cav1α, which also show long cilia, have a disrupted actin cytoskeleton and reduced RhoA GTPase activity at the apical membrane, and a greater accumulation of Rab11 vesicles at the centrosome. Subsequent experiments showed that DIA1 and ROCK help regulate ciliary length. Since MDCK cells lack apical caveolae, our results imply that non-caveolar apical Cav1α is an important regulator of ciliary length, exerting its effect via RhoA and its effectors, ROCK and DIA1.
The base of the primary cilium contains a zone of condensed membranes whose importance is not known. Here, we have studied the involvement of MAL, a tetraspanning protein that exclusively partitions into condensed membrane fractions, in the condensation of membranes at the ciliary base and investigated the importance of these membranes in primary cilium formation. We show that MAL accumulates at the ciliary base of epithelial MDCK cells. Knockdown of MAL expression resulted in a drastic reduction in the condensation of membranes at the ciliary base, the percentage of ciliated cells and the length of the cilia, but did not affect the docking of the centrosome to the plasma membrane or produce missorting of proteins to the pericentriolar zone or to the membrane of the remaining cilia. Rab8 (for which there are two isoforms, Rab8A and Rab8b), IFT88 and IFT20, which are important components of the machinery of ciliary growth, were recruited normally to the ciliary base of MAL-knockdown cells but were unable to elongate the primary cilium correctly. MAL, therefore, is crucial for the proper condensation of membranes at the ciliary base, which is required for efficient primary cilium extension.
Primary cilia are solitary, microtubule-based protrusions surrounded by a ciliary membrane equipped with selected receptors that orchestrate important signaling pathways that control cell growth, differentiation, development and homeostasis. Depending on the cell type, primary cilium assembly takes place intracellularly or at the cell surface. The intracellular route has been the focus of research on primary cilium biogenesis, whereas the route that occurs at the cell surface, which we call the “alternative” route, has been much less thoroughly characterized. In this review, based on recent experimental evidence, we present a model of primary ciliogenesis by the alternative route in which the remnant of the midbody generated upon cytokinesis acquires compact membranes, that are involved in compartmentalization of biological membranes. The midbody remnant delivers part of those membranes to the centrosome in order to assemble the ciliary membrane, thereby licensing primary cilium formation. The midbody remnant's involvement in primary cilium formation, the regulation of its inheritance by the ESCRT machinery, and the assembly of the ciliary membrane from the membranes originally associated with the remnant are discussed in the context of the literature concerning the ciliary membrane, the emerging roles of the midbody remnant, the regulation of cytokinesis, and the role of membrane compartmentalization. We also present a model of cilium emergence during evolution, and summarize the directions for future research.
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