Abstract
Epithelial cells are the most common cell type in all animals, forming the sheets and tubes that compose most organs and tissues. Apical–basal polarity is essential for epithelial cell form and function, as it determines the localization of the adhesion molecules that hold the cells together laterally and the occluding junctions that act as barriers to paracellular diffusion. Polarity must also target the secretion of specific cargoes to the apical, lateral or basal membranes and organize the cytoskeleton and internal architecture of the cell. Apical–basal polarity in many cells is established by conserved polarity factors that define the apical (Crumbs, Stardust/PALS1, aPKC, PAR-6 and CDC42), junctional (PAR-3) and lateral (Scribble, DLG, LGL, Yurt and RhoGAP19D) domains, although recent evidence indicates that not all epithelia polarize by the same mechanism. Research has begun to reveal the dynamic interactions between polarity factors and how they contribute to polarity establishment and maintenance. Elucidating these mechanisms is essential to better understand the roles of apical–basal polarity in morphogenesis and how defects in polarity contribute to diseases such as cancer.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Nowotschin, S. et al. The emergent landscape of the mouse gut endoderm at single-cell resolution. Nature 569, 361–367 (2019).
Kemphues, K. J., Priess, J. R., Morton, D. G. & Cheng, N. S. Identification of genes required for cytoplasmic localization in early C. elegans embryos. Cell 52, 311–320 (1988).
Bilder, D. & Perrimon, N. Localization of apical epithelial determinants by the basolateral PDZ protein Scribble. Nature 403, 676–680 (2000).
Tepass, U. & Knust, E. crumbs and stardust act in a genetic pathway that controls the organization of epithelia in Drosophila melanogaster. Dev. Biol. 159, 311–326 (1993).
Muller, H. & Wieschaus, E. armadillo, bazooka, and stardust are critical for early stages in formation of the zonula adherens and maintenance of the polarized blastoderm epithelium in Drosophila. J. Cell Biol. 134, 149–163 (1996).
Kim, S. et al. Kinase-activity-independent functions of atypical protein kinase C in Drosophila. J. Cell Sci. 122, 3759–3771 (2009).
Wodarz, A., Ramrath, A., Grimm, A. & Knust, E. Drosophila atypical protein kinase C associates with Bazooka and controls polarity of epithelia and neuroblasts. J. Cell Biol. 150, 1361–1374 (2000).
Petronczki, M. & Knoblich, J. A. DmPAR-6 directs epithelial polarity and asymmetric cell division of neuroblasts in Drosophila. Nat. Cell Biol. 3, 43–49 (2001).
Hutterer, A., Betschinger, J., Petronczki, M. & Knoblich, J. A. Sequential roles of Cdc42, Par-6, aPKC, and Lgl in the establishment of epithelial polarity during Drosophila embryogenesis. Dev. Cell 6, 845–854 (2004).
Huynh, J.-R., Petronczki, M., Knoblich, J. A. & St Johnston, D. Bazooka and PAR-6 are required with PAR-1 for the maintenance of oocyte fate in Drosophila. Curr. Biol. 11, 901–906 (2001).
Chen, X. & Macara, I. G. Par-3 controls tight junction assembly through the Rac exchange factor Tiam1. Nat. Cell Biol. 7, 262–269 (2005).
Yamanaka, T., Horikoshi, Y., Izumi, N. & Suzuki, A. Lgl mediates apical domain disassembly by suppressing the PAR-3–aPKC–PAR-6 complex to orient apical membrane polarity. J. Cell Sci. 119, 2107–2118 (2006).
Horikoshi, Y. et al. Interaction between PAR-3 and the aPKC–PAR-6 complex is indispensable for apical domain development of epithelial cells. J. Cell Sci. 122, 1595–1606 (2009).
Hirose, T. et al. PAR3 is essential for cyst-mediated epicardial development by establishing apical cortical domains. Development 133, 1389–1398 (2006).
Choi, J., Troyanovsky, R. B., Indra, I., Mitchell, B. J. & Troyanovsky, S. M. Scribble, Erbin, and Lano redundantly regulate epithelial polarity and apical adhesion complex. J. Cell Biol. 218, 2277–2293 (2019). This paper shows that single knockouts of mammalian Scribble orthologues have no effect on apical–basal polarity in a colon cell line, whereas simultaneous knockouts of three orthologues disrupt polarity, demonstrating that they are functionally redundant.
Assémat, E., Bazellières, E., Pallesi-Pocachard, E., Bivic, Ale & Massey-Harroche, D. Polarity complex proteins. Biochim. Biophys. Acta 1778, 614–630 (2008).
Bulgakova, N. A. & Knust, E. The Crumbs complex: from epithelial-cell polarity to retinal degeneration. J. Cell Sci. 122, 2587–2596 (2009).
Krahn, M. P., Bückers, J., Kastrup, L. & Wodarz, A. Formation of a Bazooka–Stardust complex is essential for plasma membrane polarity in epithelia. J. Cell Biol. 190, 751–760 (2010).
Nagai-Tamai, Y., Mizuno, K., Hirose, T., Suzuki, A. & Ohno, S. Regulated protein–protein interaction between aPKC and PAR-3 plays an essential role in the polarization of epithelial cells. Genes Cells 7, 1161–1171 (2002).
Betschinger, J., Mechtler, K. & Knoblich, J. The Par complex directs asymmetric cell division by phosphorylating the cytoskeletal protein Lgl. Nature 422, 326–330 (2003).
Plant, P. J. et al. A polarity complex of mPar-6 and atypical PKC binds, phosphorylates and regulates mammalian Lgl. Nat. Cell Biol. 5, 301–308 (2003).
Yamanaka, T., Horikoshi, Y., Sugiyama, Y. & Ishiyama, C. Mammalian Lgl forms a protein complex with Par-6 and aPKC independently of Par-3 to regulate epithelial cell polarity. Curr. Biol. 13, 734–734 (2003).
Hurov, J. B., Watkins, J. L. & Piwnica-Worms, H. Atypical PKC phosphorylates PAR-1 kinases to regulate localization and activity. Curr. Biol. 14, 736–741 (2004).
Suzuki, A. et al. aPKC acts upstream of PAR-1b in both the establishment and maintenance of mammalian epithelial polarity. Curr. Biol. 14, 1425–1435 (2004).
Gamblin, C. L., Hardy, E. J.-L., Chartier, F. J.-M., Bisson, N. & Laprise, P. A bidirectional antagonism between aPKC and Yurt regulates epithelial cell polarity. J. Cell Biol. 204, 487–495 (2014).
Morais-de-Sa, E., Mirouse, V. & St Johnston, D. aPKC phosphorylation of Bazooka defines the apical/lateral border in Drosophila epithelial cells. Cell 141, 509–523 (2010).
Suzuki, A. et al. aPKC kinase activity is required for the asymmetric differentiation of the premature junctional complex during epithelial cell polarization. J. Cell Sci. 115, 3565–3573 (2002).
Graybill, C., Wee, B., Atwood, S. X. & Prehoda, K. E. Partitioning-defective protein 6 (Par-6) activates atypical protein kinase C (aPKC) by pseudosubstrate displacement. J. Biol. Chem. 287, 21003–21011 (2012). This in vitro study demonstrates that Par-6 binding to aPKC activates the latter’s kinase activity by disrupting the inhibitory interaction between the PS and kinase domains of aPKC.
Dong, W. et al. A polybasic domain in aPKC mediates Par6-dependent control of membrane targeting and kinase activity. J. Cell Biol. 219, e201903031 (2020). This work shows that the PS domain of aPKC binds to lipids in the plasma membrane once it is exposed by Par-6 binding.
Joberty, G., Petersen, C., Gao, L. & Macara, I. The cell-polarity protein Par6 links Par3 and atypical protein kinase C to Cdc42. Nat. Cell Biol. 2, 531–539 (2000).
Lin, D. et al. A mammalian PAR-3–PAR-6 complex implicated in Cdc42/Rac1 and aPKC signalling and cell polarity. Nat. Cell Biol. 2, 540–547 (2000).
Peterson, F. C., Penkert, R. R., Volkman, B. F. & Prehoda, K. E. Cdc42 regulates the Par-6 PDZ domain through an allosteric CRIB-PDZ transition. Mol. Cell 13, 665–676 (2004).
Almeida, F. N., de, Walther, R. F., Pressé, M. T., Vlassaks, E. & Pichaud, F. Cdc42 defines apical identity and regulates epithelial morphogenesis by promoting apical recruitment of Par6–aPKC and Crumbs. Development 146, dev175497 (2019).
Hayase, J. et al. The WD40 protein Morg1 facilitates Par6–aPKC binding to Crb3 for apical identity in epithelial cells. J. Cell Biol. 200, 635–650 (2013).
Whitney, D. S. et al. Binding of Crumbs to the Par-6 CRIB-PDZ module is regulated by Cdc42. Biochemistry 55, 1455–1461 (2016).
Tepass, U., Theres, C. & Knust, E. crumbs encodes an EGF-like protein expressed on apical membranes of Drosophila epithelial cells and required for organization of epithelia. Cell 61, 787–799 (1990).
Wodarz, A., Hinz, U., Engelbert, M. & Knust Expression of Crumbs confers apical character on plasma membrane domains of ectodermal epithelia of Drosophila. Cell 82, 67–76 (1995).
Roh, M. H. & Margolis, B. Composition and function of PDZ protein complexes during cell polarization. Am. J. Physiol. Ren. Physiol. 285, F377–F387 (2003).
Chalmers, A., Pambos, M., Mason, J., Lang, S. & Wylie, C. aPKC, Crumbs3 and Lgl2 control apicobasal polarity in early vertebrate development. Development 132, 977–986 (2005).
Kempkens, O. et al. Computer modelling in combination with in vitro studies reveals similar binding affinities of Drosophila Crumbs for the PDZ domains of Stardust and DmPar-6. Eur. J. Cell Biol. 85, 753–767 (2006).
Waaijers, S., Ramalho, J. J., Koorman, T., Kruse, E. & Boxem, M. The C. elegans Crumbs family contains a CRB3 homolog and is not essential for viability. Biol. Open. 4, 276–284 (2015).
Campbell, K., Knust, E. & Skaer, H. Crumbs stabilises epithelial polarity during tissue remodelling. J. Cell Sci. 122, 2604–2612 (2009).
Xiao, Z. et al. Deficiency in Crumbs homolog 2 (Crb2) affects gastrulation and results in embryonic lethality in mice. Dev. Dyn. 240, 2646–2656 (2011).
Whiteman, E. L. et al. Crumbs3 is essential for proper epithelial development and viability. Mol. Cell Biol. 34, 43–56 (2014).
Szymaniak, A. D., Mahoney, J. E., Cardoso, W. V. & Varelas, X. Crumbs3-mediated polarity directs airway epithelial cell fate through the Hippo pathway effector Yap. Dev. Cell 34, 283–296 (2015).
Salis, P. et al. Crumbs, Moesin and Yurt regulate junctional stability and dynamics for a proper morphogenesis of the Drosophila pupal wing epithelium. Sci. Rep. 7, 1–14 (2017).
Lattner, J., Leng, W., Knust, E., Brankatschk, M. & Flores-Benitez, D. Crumbs organizes the transport machinery by regulating apical levels of PI(4,5)P2 in Drosophila. eLife 8, e50900 (2019).
Mangeol, P., Massey-Harroche, D., Richard, F., Lenne, P.-F. & Bivic, Ale Super-resolution imaging uncovers the nanoscopic segregation of polarity proteins in epithelia. Preprint at bioRxiv https://doi.org/10.1101/2020.08.12.248674 (2020).
Tepass, U. Crumbs, a component of the apical membrane, is required for zonula adherens formation in primary epithelia of Drosophila. Dev. Biol. 177, 217–225 (1996).
Hafezi, Y., Bosch, J. A. & Hariharan, I. K. Differences in levels of the transmembrane protein Crumbs can influence cell survival at clonal boundaries. Dev. Biol. 368, 358–369 (2012).
Pocha, S. M. & Knust, E. Complexities of Crumbs function and regulation in tissue morphogenesis. Curr. Biol. 23, R289–R293 (2013).
Zou, J., Wang, X. & Wei, X. Crb apical polarity proteins maintain zebrafish retinal cone mosaics via intercellular binding of their extracellular domains. Dev. Cell 22, 1261–1274 (2012).
Makarova, O., Roh, M. H., Liu, C.-J., Laurinec, S. & Margolis, B. Mammalian Crumbs3 is a small transmembrane protein linked to protein associated with Lin-7 (Pals1). Gene 302, 21–29 (2003).
Lemmers, C. et al. CRB3 binds directly to Par6 and regulates the morphogenesis of the tight junctions in mammalian epithelial cells. Mol. Biol. Cell 15, 4148–4165 (2004).
Tan, B. et al. The mammalian Crumbs complex defines a distinct polarity domain apical of epithelial tight junctions. Curr. Biol. 30, 2791–2804.e6 (2020). This paper uses proximity proteomics and electron microscopy in mammalian epithelia to show that the Crumbs complex localizes above tight junctions in ‘the vertebrate marginal zone’.
Iden, S. et al. aPKC phosphorylates JAM-A at Ser285 to promote cell contact maturation and tight junction formation. J. Cell Biol. 196, 623–639 (2012).
Jain, S., Suzuki, T., Seth, A., Samak, G. & Rao, R. Protein kinase Cζ phosphorylates Occludin and promotes assembly of epithelial tight junctions. Biochem. J. 437, 289–299 (2011).
Georgiou, M., Marinari, E., Burden, J. & Baum, B. Cdc42, Par6, and aPKC regulate Arp2/3-mediated endocytosis to control local adherens junction stability. Curr. Biol. 18, 1631–1638 (2008).
Harris, K. P. & Tepass, U. Cdc42 and Par proteins stabilize dynamic adherens junctions in the Drosophila neuroectoderm through regulation of apical endocytosis. J. Cell Biol. 183, 1129–1143 (2008).
Sotillos, S., Díaz-Meco, M. T., Caminero, E., Moscat, J. & Campuzano, S. DaPKC-dependent phosphorylation of Crumbs is required for epithelial cell polarity in Drosophila. J. Cell Biol. 166, 549–557 (2004).
Cao, H. et al. FERM domain phosphorylation and endogenous 3′ UTR are not essential for regulating the function and subcellular localization of polarity protein Crumbs. J. Genet. Genomics 44, 409–412 (2017).
Nakayama, M. et al. Spatial regulation of VEGF receptor endocytosis in angiogenesis. Nat. Cell Biol. 15, 249–260 (2013).
Coopman, P. & Djiane, A. Adherens junction and E-Cadherin complex regulation by epithelial polarity. Cell Mol. Life Sci. 73, 3535–3553 (2016).
Harris, T. J. & Peifer, M. The positioning and segregation of apical cues during epithelial polarity establishment in Drosophila. J. Cell Biol. 170, 813–823 (2005).
Ooshio, T. et al. Cooperative roles of Par-3 and afadin in the formation of adherens and tight junctions. J. Cell Sci. 120, 2352–2365 (2007).
Fanning, A. S. et al. The unique-5 and -6 motifs of ZO-1 regulate tight junction strand localization and scaffolding properties. Mol. Biol. Cell 18, 721–731 (2007).
Fanning, A. S. & Anderson, J. M. Zonula occludens-1 and -2 are cytosolic scaffolds that regulate the assembly of cellular junctions. Ann. NY Acad. Sci. 1165, 113–120 (2009).
Umeda, K. et al. ZO-1 and ZO-2 independently determine where claudins are polymerized in tight-junction strand formation. Cell 126, 741–754 (2006).
Matsuzawa, K. et al. MAGIs regulate aPKC to enable balanced distribution of intercellular tension for epithelial sheet homeostasis. Commun. Biol. 4, 337 (2021).
Cong, W. et al. ASPP2 regulates epithelial cell polarity through the PAR complex. Curr. Biol. 20, 1408–1414 (2010).
Sottocornola, R. et al. ASPP2 binds Par-3 and controls the polarity and proliferation of neural progenitors during CNS development. Dev. Cell 19, 126–137 (2010).
Beutel, O., Maraspini, R., Pombo-García, K., Martin-Lemaitre, C. & Honigmann, A. Phase separation of zonula occludens proteins drives formation of tight junctions. Cell 179, 923–936.e11 (2019). This in vitro study demonstrates that ZO proteins form phase-separated condensates that recruit tight junction proteins and organize the junctions.
Liu, Z. et al. Par complex cluster formation mediated by phase separation. Nat. Commun. 11, 2266 (2020). This work shows that Bazooka/Par-3 forms phase-separated condensates and that this is enhanced by Par-6, but inhibited by aPKC phosphorylation of Bazooka.
Kono, K. et al. Reconstruction of Par-dependent polarity in apolar cells reveals a dynamic process of cortical polarization. eLife 8, 386 (2019).
Schwayer, C. et al. Mechanosensation of tight junctions depends on ZO-1 phase separation and flow. Cell 179, 937–952.e18 (2019). This paper shows that ZO-1 forms phase-separated condensates at the boundary between the enveloping cell layer and the yolk syncytial layer during epiboly in the zebrafish embryo.
Benton, R. & St Johnston, D. A conserved oligomerization domain in Drosophila Bazooka/PAR-3 is important for apical localization and epithelial polarity. Curr. Biol. 13, 1330–1334 (2003).
Mizuno, K. et al. Self-association of PAR-3-mediated by the conserved N-terminal domain contributes to the development of epithelial tight junctions. J. Biol. Chem. 278, 31240–31250 (2003).
Feng, W., Wu, H., Chan, L.-N. & Zhang, M. The Par-3 NTD adopts a PB1-like structure required for Par-3 oligomerization and membrane localization. EMBO J. 26, 2786–2796 (2007).
Wei, S.-Y. et al. Echinoid is a component of adherens junctions that cooperates with DE-Cadherin to mediate cell adhesion. Dev. Cell 8, 493–504 (2005).
Zaessinger, S., Zhou, Y., Bray, S. J., Tapon, N. & Djiane, A. Drosophila MAGI interacts with RASSF8 to regulate E-Cadherin-based adherens junctions in the developing eye. Development 142, 1102–1112 (2015).
Manning, L. A., Perez-Vale, K. Z., Schaefer, K. N., Sewell, M. T. & Peifer, M. The Drosophila Afadin and ZO-1 homologues Canoe and Polychaetoid act in parallel to maintain epithelial integrity when challenged by adherens junction remodeling. Mol. Biol. Cell 30, 1938–1960 (2019).
Krahn, M. P., Klopfenstein, D. R., Fischer, N. & Wodarz, A. Membrane targeting of Bazooka/PAR-3 is mediated by direct binding to phosphoinositide lipids. Curr. Biol. 20, 636–642 (2010).
Horikoshi, Y., Hamada, S., Ohno, S. & Suetsugu, S. Phosphoinositide binding by Par-3 involved in Par-3 localization. Cell Struct. Funct. 36, 97–102 (2011).
Claret, S., Jouette, J., Benoit, B., Legent, K. & Guichet, A. PI(4,5)P2 produced by the PI4P5K SKTL controls apical size by tethering PAR-3 in Drosophila epithelial cells. Curr. Biol. 24, 1071–1079 (2014).
Wu, H. et al. PDZ domains of Par-3 as potential phosphoinositide signaling integrators. Mol. Cell 28, 886–898 (2007).
Ebnet, K. et al. The cell polarity protein ASIP/PAR-3 directly associates with junctional adhesion molecule (JAM). EMBO J. 20, 3738–3748 (2001).
Ebnet, K., Aurrand-Lions, M., Kuhn, A., Kiefer, F. & Butz, S. The junctional adhesion molecule (JAM) family members JAM-2 and JAM-3 associate with the cell polarity protein PAR-3: a possible role for JAMs in endothelial cell polarity. J. Cell Sci. 116, 3879–3891 (2003).
Takekuni, K. et al. Direct binding of cell polarity protein PAR-3 to cell–cell adhesion molecule Nectin at neuroepithelial cells of developing mouse. J. Biol. Chem. 278, 5497–5500 (2003).
Renschler, F. A. et al. Structural basis for the interaction between the cell polarity proteins Par3 and Par6. Sci. Signal. 11, eaam9899 (2018).
Qin, Y., Capaldo, C., Gumbiner, B. M. & Macara, I. G. The mammalian Scribble polarity protein regulates epithelial cell adhesion and migration through E-cadherin. J. Cell Biol. 171, 1061–1071 (2005).
Ivanov, A. I. et al. Tumor suppressor Scribble regulates assembly of tight junctions in the intestinal epithelium. Am. J. Pathol. 176, 134–145 (2010).
Sripathy, S., Lee, M. & Vasioukhin, V. Mammalian Llgl2 is necessary for proper branching morphogenesis during placental development. Mol. Cell Biol. 31, 2920–2933 (2011).
Russ, A., Louderbough, J. M. V., Zarnescu, D. & Schroeder, J. A. Hugl1 and Hugl2 in mammary epithelial cells: polarity, proliferation, and differentiation. PLoS ONE 7, e47734 (2012).
Montcouquiol, M. et al. Identification of Vangl2 and Scrb1 as planar polarity genes in mammals. Nature 423, 173–177 (2003).
Yates, L. L. et al. Scribble is required for normal epithelial cell–cell contacts and lumen morphogenesis in the mammalian lung. Dev. Biol. 373, 267–280 (2013).
Murdoch, J. N. et al. Disruption of Scribble (Scrb1) causes severe neural tube defects in the circletail mouse. Hum. Mol. Genet. 12, 87–98 (2003).
Lesko, A. C., Keller, R., Chen, P. & Sutherland, A. Scribble mutation disrupts convergent extension and apical constriction during mammalian neural tube closure. Dev. Biol. 478, 59–75 (2021).
Pearson, H. B. et al. SCRIB expression is deregulated in human prostate cancer, and its deficiency in mice promotes prostate neoplasia. J. Clin. Invest. 121, 4257–4267 (2011).
Elsum, I. A. et al. Scrib heterozygosity predisposes to lung cancer and cooperates with KRas hyperactivation to accelerate lung cancer progression in vivo. Oncogene 33, 5523–5533 (2014).
Godde, N. J. et al. Scribble modulates the MAPK/Fra1 pathway to disrupt luminal and ductal integrity and suppress tumour formation in the mammary gland. PLoS Genet. 10, e1004323 (2014).
Stephens, R. et al. The Scribble cell polarity module in the regulation of cell signaling in tissue development and tumorigenesis. J. Mol. Biol. 430, 3585–3612 (2018).
Stevens, P. D. et al. Erbin suppresses KSR1-mediated RAS/RAF signaling and tumorigenesis in colorectal cancer. Cancer Res. 78, 4839–4892 (2018).
Bilder, D., Schober, M. & Perrimon, N. Integrated activity of PDZ protein complexes regulates epithelial polarity. Nat. Cell Biol. 5, 53–58 (2003).
Tanentzapf, G. & Tepass, U. Interactions between the crumbs, lethal giant larvae and bazooka pathways in epithelial polarization. Nat. Cell Biol. 5, 46–52 (2003).
Oshima, K. & Fehon, R. G. Analysis of protein dynamics within the septate junction reveals a highly stable core protein complex that does not include the basolateral polarity protein Discs large. J. Cell Sci. 124, 2861–2871 (2011).
Khoury, M. J. & Bilder, D. Distinct activities of Scrib module proteins organize epithelial polarity. Proc. Natl Acad. Sci. USA 117, 11531–11540 (2020).
Lu, J., Dong, W., Tao, Y. & Hong, Y. Electrostatic plasma membrane targeting contributes to Dlg function in cell polarity and tumorigenesis. Development 148, dev196956 (2021).
Caria, S. et al. Drosophila melanogaster Guk-holder interacts with the Scribbled PDZ1 domain and regulates epithelial development with Scribbled and Discs large. J. Biol. Chem. 293, 4519–4531 (2018).
Awadia, S. et al. SGEF forms a complex with Scribble and Dlg1 and regulates epithelial junctions and contractility. J. Cell Biol. 218, 2699–2725 (2019).
Lockwood, C. A., Lynch, A. M. & Hardin, J. Dynamic analysis identifies novel roles for DLG-1 subdomains in AJM-1 recruitment and LET-413-dependent apical focusing. J. Cell Sci. 121, 1477–1487 (2008).
Li, Y., Karnak, D., Demeler, B., Margolis, B. & Lavie, A. Structural basis for L27 domain-mediated assembly of signaling and cell polarity complexes. EMBO J. 23, 2723–2733 (2004).
Ghosh, A., Ramagopal, U. A., Bonanno, J. B., Brenowitz, M. & Almo, S. C. Structures of the L27 domain of Disc large homologue 1 protein illustrate a self-assembly module. Biochemistry 57, 1293–1305 (2018).
Ventura, G., Moreira, S., Barros-Carvalho, A., Osswald, M. & Morais-de-Sá, E. Lgl cortical dynamics are independent of binding to the Scrib–Dlg complex but require Dlg-dependent restriction of aPKC. Development 147, dev186593 (2020). This work shows that Lgl is not part of the Scribble complex but requires Dlg to protect it from aPKC phosphorylation.
Dong, W. et al. A conserved polybasic domain mediates plasma membrane targeting of Lgl and its regulation by hypoxia. J. Cell Biol. 211, 273–286 (2015).
Bailey, M. J. & Prehoda, K. E. Establishment of Par-polarized cortical domains via phosphoregulated membrane motifs. Dev. Cell 35, 199–210 (2015). Along with the work by Dong et al. (2015), this paper shows that Lgl binds to the plasma membrane through a central polybasic domain and that aPKC phosphorylates this domain to inhibit membrane binding, providing an explanation for how aPKC excludes Lgl from the apical membrane.
Kallay, L. M., McNickle, A., Brennwald, P. J., Hubbard, A. L. & Braiterman, L. T. Scribble associates with two polarity proteins, Lgl2 and Vangl2, via distinct molecular domains. J. Cell Biochem. 99, 647–664 (2006).
Böhm, H., Brinkmann, V., Drab, M., Henske, A. & Kurzchalia, T. V. Mammalian homologues of C. elegans PAR-1 are asymmetrically localized in epithelial cells and may influence their polarity. Curr. Biol. 7, 603–606 (1997).
Cox, D. N., Lu, B., Sun, T.-Q., Williams, L. T. & Jan, Y.-N. Drosophila Par-1 is required for oocyte differentiation and microtubule organization. Curr. Biol. 11, 75–87 (2001).
Doerflinger, H., Benton, R., Shulman, J. M. & St Johnston, D. The role of PAR-1 in regulating the polarised microtubule cytoskeleton in the Drosophila follicular epithelium. Development 130, 3965–3975 (2003).
Benton, R. & St Johnston, D. Drosophila PAR-1 and 14-3-3 inhibit Bazooka/PAR-3 to establish complementary cortical domains in polarized cells. Cell 115, 691–704 (2003).
Aguilar-Aragon, M. et al. Pak1 kinase maintains apical membrane identity in epithelia. Cell Rep. 22, 1639–1646 (2018).
Hannaford, M., Loyer, N., Tonelli, F., Zoltner, M. & Januschke, J. A chemical-genetics approach to study the role of atypical Protein Kinase C in Drosophila. Development 146, dev170589 (2019).
Soriano, E. V. et al. aPKC inhibition by Par3 CR3 flanking regions controls substrate access and underpins apical-junctional polarization. Dev. Cell 38, 384–398 (2016).
Holly, R. W. & Prehoda, K. E. Phosphorylation of Par-3 by atypical Protein Kinase C and competition between its substrates. Dev. Cell 49, 678–679 (2019).
Carvalho, C. A., Moreira, S., Ventura, G., Sunkel, C. E. & Morais-de-Sá, E. Aurora A triggers Lgl cortical release during symmetric division to control planar spindle orientation. Curr. Biol. 25, 53–60 (2015).
Wirtz-Peitz, F., Nishimura, T. & Knoblich, J. A. Linking cell cycle to asymmetric division: Aurora-A phosphorylates the Par complex to regulate Numb localization. Cell 135, 161–173 (2008).
Fic, W. et al. RhoGAP19D inhibits Cdc42 laterally to control epithelial cell shape and prevent invasion. J. Cell Biol. 220, e202009116 (2021). This work demonstrates that RhoGAP19D is recruited to the lateral membrane by Cadherin adhesion complexes where it inactivates Cdc42, thereby coupling cell–cell adhesion to the apical restriction of Cdc42 activity.
Gamblin, C. L. et al. Oligomerization of the FERM-FA protein Yurt controls epithelial cell polarity. J. Cell Biol. 217, 3853–3862 (2018).
Nakajima, H. & Tanoue, T. Lulu2 regulates the circumferential actomyosin tensile system in epithelial cells through p114RhoGEF. J. Cell Biol. 195, 245–261 (2011).
Laprise, P. et al. The FERM protein Yurt is a negative regulatory component of the Crumbs complex that controls epithelial polarity and apical membrane size. Dev. Cell 11, 363–374 (2006).
Laprise, P. et al. Yurt, Coracle, Neurexin IV and the Na+,K+-ATPase form a novel group of epithelial polarity proteins. Nature 459, 1141 (2009).
Walther, R. F. & Pichaud, F. Crumbs/DaPKC-dependent apical exclusion of Bazooka promotes photoreceptor polarity remodeling. Curr. Biol. 20, 1065–1074 (2010).
Pelaseyed, T. & Bretscher, A. Regulation of actin-based apical structures on epithelial cells. J. Cell Sci. 131, jcs221853 (2018).
Klebes, A. & Knust, E. A conserved motif in Crumbs is required for E-cadherin localisation and zonula adherens formation in Drosophila. Curr. Biol. 10, 76–85 (2000).
Wei, Z., Li, Y., Ye, F. & Zhang, M. Structural basis for the phosphorylation-regulated interaction between the cytoplasmic tail of cell polarity protein Crumbs and the actin-binding protein Moesin. J. Biol. Chem. 290, 11384–11392 (2015).
Médina, E. et al. Crumbs interacts with Moesin and βHeavy-spectrin in the apical membrane skeleton of Drosophila. J. Cell Biol. 158, 941–951 (2002).
Pellikka, M. et al. Crumbs, the Drosophila homologue of human CRB1/RP12, is essential for photoreceptor morphogenesis. Nature 416, 143–149 (2002).
Ling, C. et al. The apical transmembrane protein Crumbs functions as a tumor suppressor that regulates Hippo signaling by binding to Expanded. Proc. Natl Acad. Sci. USA 107, 10532–10537 (2010).
Robinson, B. S., Huang, J., Hong, Y. & Moberg, K. H. Crumbs regulates Salvador/Warts/Hippo signaling in Drosophila via the FERM-domain protein Expanded. Curr. Biol. 20, 582–590 (2010).
Hoover, K. & Bryant, P. Drosophila Yurt is a new protein-4.1-like protein required for epithelial morphogenesis. Dev. Genes Evol. 212, 230–238 (2002).
Biehler, C. et al. Pak1 and PP2A antagonize aPKC function to support cortical tension induced by the Crumbs–Yurt complex. eLife 10, e67999 (2021). This paper shows that the apical localization of Yurt promotes cortical tension and apical constriction.
Silver, J. T. et al. Apical polarity proteins recruit the RhoGEF Cysts to promote junctional myosin assembly. J. Cell Biol. 218, 3397–3414 (2019).
Zihni, C. et al. An apical MRCK-driven morphogenetic pathway controls epithelial polarity. Nat. Cell Biol. 19, 1049–1060 (2017).
Watson, J. R., Owen, D. & Mott, H. R. Cdc42 in actin dynamics: an ordered pathway governed by complex equilibria and directional effector handover. Small GTPases 8, 237–244 (2016).
Hinze, C. & Boucrot, E. Local actin polymerization during endocytic carrier formation. Biochem. Soc. Trans. 46, 565–576 (2018).
Leibfried, A., Fricke, R., Morgan, M. J., Bogdan, S. & Bellaïche, Y. Drosophila Cip4 and WASp define a branch of the Cdc42–Par6–aPKC pathway regulating E-cadherin endocytosis. Curr. Biol. 18, 1639–1648 (2008).
Mège, R. M. & Ishiyama, N. Integration of Cadherin adhesion and cytoskeleton at adherens junctions. Cold Spring Harb. Perspect. Biol. 9, a028738 (2017).
Desai, R. et al. Monomeric α-catenin links cadherin to the actin cytoskeleton. Nat. Cell Biol. 15, 261–273 (2013).
Spadaro, D. et al. Tension-dependent stretching activates ZO-1 to control the junctional localization of its interactors. Curr. Biol. 27, 3783–3795.e8 (2017).
Citi, S. The mechanobiology of tight junctions. Biophys. Rev. 11, 783–793 (2019).
Nishimura, T., Yamaguchi, T., Kato, K. & Yoshizawa, M. PAR-6–PAR-3 mediates Cdc42-induced Rac activation through the Rac GEFs STEF/Tiam1. Nat. Cell Biol. 7, 270–276 (2005).
Georgiou, M. & Baum, B. Polarity proteins and Rho GTPases cooperate to spatially organise epithelial actin-based protrusions. J. Cell Sci. 123, 1089–1098 (2010).
Matsuzawa, K. et al. PAR3–aPKC regulates Tiam1 by modulating suppressive internal interactions. Mol. Biol. Cell 27, 1511–1523 (2016).
Ohara, K. et al. Involvement of Girdin in the determination of cell polarity during cell migration. PLoS ONE 7, e36681 (2012).
Sasaki, K., Kakuwa, T., Akimoto, K., Koga, H. & Ohno, S. Regulation of epithelial cell polarity by PAR-3 depends on Girdin transcription and Girdin–Gαi3 signaling. J. Cell Sci. 128, 2244–2258 (2015).
Houssin, E., Tepass, U. & Laprise, P. Girdin-mediated interactions between cadherin and the actin cytoskeleton are required for epithelial morphogenesis in Drosophila. Development 142, 1777–1784 (2015).
Biehler, C. et al. Girdin is a component of the lateral polarity protein network restricting cell dissemination. PLoS Genet. 16, e1008674 (2020).
Khanal, I., Elbediwy, A., Loza, M. D. C. D., de la, Fletcher, G. C. & Thompson, B. J. Shot and Patronin polarise microtubules to direct membrane traffic and biogenesis of microvilli in epithelia. J. Cell Sci. 129, 2651–2659 (2016).
Zajac, A. L. & Horne-Badovinac, S. Kinesin-directed secretion of basement membrane proteins to a subdomain of the basolateral surface in Drosophila epithelial cells. Curr. Biol. 32, 735–748.e10 (2022). This work shows that kinesins 1 and 3 direct the secretion of collagen to the basal portion of the lateral domain in follicle cells. When both kinesins are removed, collagen accumulates apically, indicating that the site of ECM secretion is determined by transport along polarized microtubules.
Tanaka, N., Meng, W., Nagae, S. & Takeichi, M. Nezha/CAMSAP3 and CAMSAP2 cooperate in epithelial-specific organization of noncentrosomal microtubules. Proc. Natl Acad. Sci. USA 109, 20029–20034 (2012).
Toya, M. et al. CAMSAP3 orients the apical-to-basal polarity of microtubule arrays in epithelial cells. Proc. Natl Acad. Sci. USA 113, 332–337 (2016). This paper shows that CAMSAP3 is required to anchor microtubule minus ends to the apical cortex of Caco-2 cells.
Nashchekin, D., Fernandes, A. R. & St Johnston, D. Patronin/Shot cortical foci assemble the noncentrosomal microtubule array that specifies the Drosophila anterior–posterior axis. Dev. Cell 38, 61–72 (2016).
Sanchez, A. D. et al. Proximity labeling reveals non-centrosomal microtubule-organizing center components required for microtubule growth and localization. Curr. Biol. 31, 3586–3600.e11 (2021).
Feldman, J. L. & Priess, J. R. A role for the centrosome and PAR-3 in the hand-off of MTOC function during epithelial polarization. Curr. Biol. 22, 575–582 (2012).
Jiang, T., McKinley, R. F. A., McGill, M. A., Angers, S. & Harris, T. J. C. A Par-1–Par-3–centrosome cell polarity pathway and its tuning for isotropic cell adhesion. Curr. Biol. 25, 2701–2708 (2015).
Hong, E., Jayachandran, P. & Brewster, R. The polarity protein Pard3 is required for centrosome positioning during neurulation. Dev. Biol. 341, 335–345 (2010).
Wheway, G., Nazlamova, L. & Hancock, J. T. Signaling through the primary cilium. Front. Cell Dev. Biol. 6, 8 (2018).
Carvajal-Gonzalez, J. M., Mulero-Navarro, S. & Mlodzik, M. Centriole positioning in epithelial cells and its intimate relationship with planar cell polarity. Bioessays 38, 1234–1245 (2016).
Donati, A., Anselme, I., Schneider-Maunoury, S. & Vesque, C. Planar polarization of cilia in the zebrafish floor-plate involves Par3-mediated posterior localization of highly motile basal bodies. Development 148, dev196386 (2021).
Jewett, C. E. et al. RAB19 directs cortical remodeling and membrane growth for primary ciliogenesis. Dev. Cell 56, 325–340.e8 (2021).
Sfakianos, J. et al. Par3 functions in the biogenesis of the primary cilium in polarized epithelial cells. J. Cell Biol. 179, 1133–1140 (2007).
Fan, S. et al. Polarity proteins control ciliogenesis via Kinesin motor interactions. Curr. Biol. 14, 1451–1461 (2004).
Fan, S. et al. A novel Crumbs3 isoform regulates cell division and ciliogenesis via importin β interactions. J. Cell Biol. 178, 387–398 (2007).
Hazime, K. & Malicki, J. J. Apico-basal polarity determinants encoded by crumbs genes affect ciliary shaft protein composition, IFT movement dynamics, and cilia length. Genetics 207, 1041–1051 (2017).
Apodaca, G., Gallo, L. I. & Bryant, D. M. Role of membrane traffic in the generation of epithelial cell asymmetry. Nat. Cell Biol. 14, 1235–1243 (2012).
Rodriguez-Boulan, E. & Macara, I. G. Organization and execution of the epithelial polarity programme. Nat. Rev. Mol. Cell Biol. 15, 225–242 (2014).
Bond, L. M., Brandstaetter, H., Sellers, J. R., Kendrick-Jones, J. & Buss, F. Myosin motor proteins are involved in the final stages of the secretory pathways. Biochem. Soc. T 39, 1115–1119 (2011).
Südhof, T. C. & Rothman, J. E. Membrane fusion: grappling with SNARE and SM proteins. Science 323, 474–477 (2009).
Pocha, S. M., Shevchenko, A. & Knust, E. Crumbs regulates rhodopsin transport by interacting with and stabilizing myosin V. J. Cell Biol. 195, 827–838 (2011).
Sharma, N., Low, S. H., Misra, S., Pallavi, B. & Weimbs, T. Apical targeting of syntaxin 3 is essential for epithelial cell polarity. J. Cell Biol. 173, 937–948 (2006).
ter Beest, M. B. A., Chapin, S. J., Avrahami, D. & Mostov, K. E. The role of syntaxins in the specificity of vesicle targeting in polarized epithelial cells. Mol. Biol. Cell 16, 5784–5792 (2005).
Wiegerinck, C. L. et al. Loss of syntaxin 3 causes variant microvillus inclusion disease. Gastroenterology 147, 65–68.e10 (2014).
Torkko, J. M., Manninen, A., Schuck, S. & Simons, K. Depletion of apical transport proteins perturbs epithelial cyst formation and ciliogenesis. J. Cell Sci. 121, 1193–1203 (2008).
Fields, I. C. et al. v-SNARE cellubrevin is required for basolateral sorting of AP-1B-dependent cargo in polarized epithelial cells. J. Cell Biol. 177, 477–488 (2007).
Vogel, G. F. et al. Cargo-selective apical exocytosis in epithelial cells is conducted by Myo5B, Slp4a, Vamp7, and Syntaxin 3. J. Cell Biol. 211, 587–604 (2015).
Zeng, J., Feng, S., Wu, B. & Guo, W. Polarized exocytosis. CSH Perspect. Biol. 9, a027870 (2017).
Lepore, D. M., Martínez-Núñez, L. & Munson, M. Exposing the elusive exocyst structure. Trends Biochem. Sci. 43, 714–725 (2018).
Ahmed, S. M. & Macara, I. G. The Par3 polarity protein is an exocyst receptor essential for mammary cell survival. Nat. Commun. 8, 14867 (2017).
Langevin, J. et al. Drosophila exocyst components Sec5, Sec6, and Sec15 regulate DE-Cadherin trafficking from recycling endosomes to the plasma membrane. Dev. Cell 9, 355–376 (2005).
Das, A. et al. RalA promotes a direct exocyst–Par6 interaction to regulate polarity in neuronal development. J. Cell Sci. 127, 686–699 (2014).
Gassama-Diagne, A. et al. Phosphatidylinositol-3,4,5-trisphosphate regulates the formation of the basolateral plasma membrane in epithelial cells. Nat. Cell Biol. 8, 963–970 (2006).
Martin-Belmonte, F. et al. PTEN-mediated apical segregation of phosphoinositides controls epithelial morphogenesis through Cdc42. Cell 128, 383–397 (2007).
Pece, S., Chiariello, M., Murga, C. & Gutkind, J. S. Activation of the protein kinase Akt/PKB by the formation of E-cadherin-mediated cell–cell junctions. J. Biol. Chem. 274, 19347–19351 (1999).
Chartier, F. J.-M., Hardy, E. J.-L. & Laprise, P. Crumbs controls epithelial integrity by inhibiting Rac1 and PI3K. J. Cell Sci. 124, 3393–3398 (2011).
Laprise, P., Viel, A. & Rivard, N. Human homolog of Disc-large is required for adherens junction assembly and differentiation of human intestinal epithelial cells. J. Biol. Chem. 279, 10157–10166 (2004).
Stein, W., von, Ramrath, A., Grimm, A., Müller-Borg, M. & Wodarz, A. Direct association of Bazooka/PAR-3 with the lipid phosphatase PTEN reveals a link between the PAR/aPKC complex and phosphoinositide signaling. Development 132, 1675–1686 (2005).
Feng, W., Wu, H., Chan, L. & Zhang, M. Par-3-mediated junctional localization of the lipid phosphatase PTEN is required for cell polarity establishment. J. Biol. Chem. 283, 23440–23449 (2008).
Román-Fernández, Á. et al. The phospholipid PI(3,4)P2 is an apical identity determinant. Nat. Commun. 9, 5041 (2018).
Zhang, H. et al. Apicobasal domain identities of expanding tubular membranes depend on glycosphingolipid biosynthesis. Nat. Cell Biol. 13, 1189–1201 (2011).
Mazumdar, A. & Mazumdar, M. How one becomes many: blastoderm cellularization in Drosophila melanogaster. Bioessays 24, 1012–1022 (2002).
Tepass, U. The apical polarity protein network in Drosophila epithelial cells: regulation of polarity, junctions, morphogenesis, cell growth, and survival. Ann. Rev. Cell Dev. Biol. 28, 655–685 (2012).
Harris, T. J. C. & Peifer, M. Adherens junction-dependent and -independent steps in the establishment of epithelial cell polarity in Drosophila. J. Cell Biol. 167, 135–147 (2004).
Choi, W., Harris, N. J., Sumigray, K. D. & Peifer, M. Rap1 and Canoe/afadin are essential for establishment of apical–basal polarity in the Drosophila embryo. Mol. Biol. Cell 24, 883–1093 (2013).
Bonello, T. T., Perez-Vale, K. Z., Sumigray, K. D. & Peifer, M. Rap1 acts via multiple mechanisms to position Canoe and adherens junctions and mediate apical–basal polarity establishment. Development 145, dev157941 (2017).
Bayraktar, J., Zygmunt, D. & Carthew, R. W. Par-1 kinase establishes cell polarity and functions in Notch signaling in the Drosophila embryo. J. Cell Sci. 119, 711–721 (2006).
McKinley, R. F. A., Yu, C. G. & Harris, T. J. C. Assembly of Bazooka polarity landmarks through a multifaceted membrane-association mechanism. J. Cell Sci. 125, 1177–1190 (2012).
Bonello, T. T., Choi, W. & Peifer, M. Scribble and Discs-large direct initial assembly and positioning of adherens junctions during the establishment of apical–basal polarity. Development 146, dev180976 (2019).
McKinley, R. F. A. & Harris, T. J. C. Displacement of basolateral Bazooka/PAR-3 by regulated transport and dispersion during epithelial polarization in Drosophila. Mol. Biol. Cell 23, 4465–4471 (2012).
Blankenship, J. T., Fuller, M. T. & Zallen, J. A. The Drosophila homolog of the Exo84 exocyst subunit promotes apical epithelial identity. J. Cell Sci. 120, 3099–3110 (2007).
Roeth, J. F., Sawyer, J. K., Wilner, D. A. & Peifer, M. Rab11 helps maintain apical crumbs and adherens junctions in the Drosophila embryonic ectoderm. PLoS ONE 4, e7634 (2009).
Harris, T. J. C. & Peifer, M. aPKC controls microtubule organization to balance adherens junction symmetry and planar polarity during development. Dev. Cell 12, 727–738 (2007).
Tepass, U. & Hartenstein, V. The development of cellular junctions in the Drosophila embryo. Dev. Biol. 161, 563–596 (1994).
Anderson, D. C., Gill, J. S., Cinalli, R. M. & Nance, J. Polarization of the C. elegans embryo by RhoGAP-mediated exclusion of PAR-6 from cell contacts. Science 320, 1771 (2008).
Klompstra, D., Anderson, D. C., Yeh, J. Y., Zilberman, Y. & Nance, J. An instructive role for C. elegans E-cadherin in translating cell contact cues into cortical polarity. Nat. Cell Biol. 17, 726–735 (2015). Together with Anderson et al. (2008), this paper shows that cadherin-dependent cell–cell adhesion establishes apical–basal polarity in worm blastomeres by recruiting the Cdc42GAP PAC-1 to inhibit CDC42 laterally. This restricts active CDC42 to the contact-free cell surface, where it recruits and activates PAR-6–aPKC.
Zhu, M., Leung, C. Y., Shahbazi, M. N. & Zernicka-Goetz, M. Actomyosin polarisation through PLC-PKC triggers symmetry breaking of the mouse embryo. Nat. Commun. 8, 921 (2017).
Zhu, M. et al. Developmental clock and mechanism of de novo polarization of the mouse embryo. Science 370, eabd2703 (2020).
Zhu, M. et al. Human embryo polarization requires PLC signaling to mediate trophectoderm specification. eLife 10, e65068 (2021).
Bryant, D. M. et al. A molecular network for de novo generation of the apical surface and lumen. Nat. Cell Biol. 12, 1035–1045 (2010).
Blasky, A. J., Mangan, A. & Prekeris, R. Polarized protein transport and lumen formation during epithelial tissue morphogenesis. Ann. Rev. Cell Dev. Biol. 31, 575–591 (2015).
Akhtar, N. & Streuli, C. H. An integrin–ILK–microtubule network orients cell polarity and lumen formation in glandular epithelium. Nat. Cell Biol. 15, 17–27 (2013).
Bedzhov, I. & Zernicka-Goetz, M. Self-organizing properties of mouse pluripotent cells initiate morphogenesis upon implantation. Cell 156, 1032–1044 (2014).
Yang, X., Zou, J., Hyde, D. R., Davidson, L. A. & Wei, X. Stepwise maturation of apicobasal polarity of the neuroepithelium is essential for vertebrate neurulation. J. Neurosci. 29, 11426–11440 (2009).
Wang, A. Z., Ojakian, G. K. & Nelson, W. J. Steps in the morphogenesis of a polarized epithelium. II. Disassembly and assembly of plasma membrane domains during reversal of epithelial cell polarity in multicellular epithelial (MDCK) cysts. J. Cell Sci. 95, 153–165 (1990).
O’Brien, L. E., Zegers, M. M. P. & Mostov, K. E. Building epithelial architecture: insights from three-dimensional culture models. Nat. Rev. Mol. Cell Biol. 3, 531–537 (2002).
Yu, W. et al. β1-Integrin orients epithelial polarity via Rac1 and laminin. Mol. Biol. Cell 16, 433–445 (2005).
Buckley, C. E. et al. Mirror-symmetric microtubule assembly and cell interactions drive lumen formation in the zebrafish neural rod. EMBO J. 32, 30–44 (2013).
Molè, M. A. et al. Integrin β1 coordinates survival and morphogenesis of the embryonic lineage upon implantation and pluripotency transition. Cell Rep. 34, 108834 (2021). This work demonstrates that β1 integrin signalling via ROCK inhibition is necessary to suppress actomyosin accumulation on the basal side of the de novo polarizing mammalian epiblast, therefore restricting apical protein accumulation to the apical side of cells.
O’Brien, L. E. et al. Rac1 orientates epithelial apical polarity through effects on basolateral laminin assembly. Nat. Cell Biol. 3, 831–838 (2001).
Yu, W. et al. Involvement of RhoA, ROCK I and myosin II in inverted orientation of epithelial polarity. EMBO Rep. 9, 923–929 (2008).
Bryant, D. M. et al. A molecular switch for the orientation of epithelial cell polarization. Dev. Cell 31, 171–187 (2014).
Jaffe, A. B., Kaji, N., Durgan, J. & Hall, A. Cdc42 controls spindle orientation to position the apical surface during epithelial morphogenesis. J. Cell Biol. 183, 625–633 (2008).
Tawk, M. et al. A mirror-symmetric cell division that orchestrates neuroepithelial morphogenesis. Nature 446, 797–800 (2007).
Gao, L. et al. Afadin orients cell division to position the tubule lumen in developing renal tubules. Development 144, 3511–3520 (2017).
Zigman, M., le, A. T., Fraser, S. E. & Moens, C. B. Zebrafish neural tube morphogenesis requires scribble-dependent oriented cell divisions. Curr. Biol. 21, 79–86 (2011).
Quesada-Hernandez, E. et al. Stereotypical cell division orientation controls neural rod midline formation in zebrafish. Curr. Biol. 20, 1966–1972 (2010).
Zigman, M., Laumann-Lipp, N., Titus, T., Postlethwait, J. & Moens, C. B. Hoxb1b controls oriented cell division, cell shape and microtubule dynamics in neural tube morphogenesis. Development 141, 639–649 (2014).
Rodriguez-Fraticelli, A. E. et al. The Cdc42 GEF Intersectin 2 controls mitotic spindle orientation to form the lumen during epithelial morphogenesis. J. Cell Biol. 189, 725–738 (2010).
Li, D., Mangan, A., Cicchini, L., Margolis, B. & Prekeris, R. FIP5 phosphorylation during mitosis regulates apical trafficking and lumenogenesis. EMBO Rep. 15, 428–437 (2014).
Rathbun, L. I. et al. Cytokinetic bridge triggers de novo lumen formation in vivo. Nat. Commun. 11, 1269 (2020).
Luján, P. et al. PRL-3 disrupts epithelial architecture by altering the post-mitotic midbody position. J. Cell Sci. 129, 4130–4142 (2016).
Schlüter, M. A. et al. Trafficking of Crumbs3 during cytokinesis is crucial for lumen formation. Mol. Biol. Cell 20, 4652–4663 (2009).
Ciruna, B., Jenny, A., Lee, D., Mlodzik, M. & Schier, A. F. Planar cell polarity signalling couples cell division and morphogenesis during neurulation. Nature 439, 220–224 (2006).
Liang, X., Weberling, A., Hii, C. Y., Zernicka-Goetz, M. & Buckley, C. E-cadherin mediated AMIS localisation. Preprint at bioRxiv https://doi.org/10.1101/2021.11.30.470571 (2022).
Herrera, A., Menendez, A., Torroba, B., Ochoa, A. & Pons, S. Dbnl and β-catenin promote pro-N-cadherin processing to maintain apico-basal polarity. J. Cell Biol. 220, e202007055 (2021).
Zhang, Y. et al. Biomimetic niches reveal the minimal cues to trigger apical lumen formation in single hepatocytes. Nat. Mater. 19, 1026–1035 (2020).
Mangan, A. J. et al. Cingulin and actin mediate midbody-dependent apical lumen formation during polarization of epithelial cells. Nat. Commun. 7, 12426 (2016). This work shows that the tight junction protein cingulin tethers FIP5 vesicles at the AMIS through its interactions with midbody microtubules.
Klinkert, K., Rocancourt, M., Houdusse, A. & Echard, A. Rab35 GTPase couples cell division with initiation of epithelial apico-basal polarity and lumen opening. Nat. Commun. 7, 11166 (2016).
Mrozowska, P. S. & Fukuda, M. Regulation of podocalyxin trafficking by Rab small GTPases in 2D and 3D epithelial cell cultures. J. Cell Biol. 213, 355–369 (2016).
Lu, R. & Wilson, J. M. Rab14 specifies the apical membrane through Arf6-mediated regulation of lipid domains and Cdc42. Sci. Rep. 6, 38249 (2016).
Blum, I. R. et al. Rab22a regulates the establishment of epithelial polarity. Small GTPases 12, 282–293 (2020).
Wang, L.-T., Rajah, A., Brown, C. M. & McCaffrey, L. CD13 orients the apical–basal polarity axis necessary for lumen formation. Nat. Commun. 12, 4697 (2021). This work shows that the transmembrane aminopeptidase CD13 acts upstream of RAB11A and RAB35 to both initiate the internalization of apical proteins from the basal membrane and localize RAB35 at the AMIS to enable apical vesicle docking.
St Johnston, D. & Sanson, B. Epithelial polarity and morphogenesis. Curr. Opin. Cell Biol. 23, 540–546 (2011).
Lemke, S. B. & Nelson, C. M. Dynamic changes in epithelial cell packing during tissue morphogenesis. Curr. Biol. 31, R1098–R1110 (2021).
He, B., Doubrovinski, K., Polyakov, O. & Wieschaus, E. Apical constriction drives tissue-scale hydrodynamic flow to mediate cell elongation. Nature 508, 392–396 (2014).
Streichan, S. J., Lefebvre, M. F., Noll, N., Wieschaus, E. F. & Shraiman, B. I. Global morphogenetic flow is accurately predicted by the spatial distribution of myosin motors. eLife 7, e27454 (2018).
Symonds, A. C., Buckley, C. E., Williams, C. A. & Clarke, J. D. W. Coordinated assembly and release of adhesions builds apical junctional belts during de novo polarisation of an epithelial tube. Development 147, dev191494 (2020).
Ramkumar, N. et al. Crumbs2 promotes cell ingression during the epithelial-to-mesenchymal transition at gastrulation. Nat. Cell Biol. 18, 1281–1291 (2016).
Tait, C. M. et al. Crumbs2 mediates ventricular layer remodelling to form the spinal cord central canal. PLoS Biol. 18, e3000470 (2020).
Röper, K. Anisotropy of Crumbs and aPKC drives myosin cable assembly during tube formation. Dev. Cell 23, 939–953 (2012).
Flores-Benitez, D. & Knust, E. Crumbs is an essential regulator of cytoskeletal dynamics and cell-cell adhesion during dorsal closure in Drosophila. eLife 4, e07398 (2015).
Letizia, A., Sotillos, S., Campuzano, S. & Llimargas, M. Regulated Crb accumulation controls apical constriction and invagination in Drosophila tracheal cells. J. Cell Sci. 124, 240–251 (2011).
Krueger, D., Tardivo, P., Nguyen, C. & Renzis, S. D. Downregulation of basal myosin-II is required for cell shape changes and tissue invagination. EMBO J. 37, e100170 (2018).
Izquierdo, E., Quinkler, T. & De Renzis, S. Guided morphogenesis through optogenetic activation of Rho signalling during early Drosophila embryogenesis. Nat. Commun. 9, 2366 (2018).
Sidor, C., Stevens, T. J., Jin, L., Boulanger, J. & Röper, K. Rho-kinase planar polarization at tissue boundaries depends on phospho-regulation of membrane residence time. Dev. Cell 52, 364–378.e7 (2020).
Wang, Y. C., Khan, Z., Kaschube, M. & Wieschaus, E. F. Differential positioning of adherens junctions is associated with initiation of epithelial folding. Nature 484, 390–393 (2012).
Weng, M. & Wieschaus, E. Polarity protein Par3/Bazooka follows myosin-dependent junction repositioning. Dev. Biol. 422, 1–10 (2017). This work shows that during fly mesoderm internalization, Bazooka is first downregulated by Snail expression and then repositioned towards the apical end of cells by actomyosin contractility.
Banerjee, J. J. et al. Meru couples planar cell polarity with apical–basal polarity during asymmetric cell division. eLife 6, e25014 (2017).
Aigouy, B. & Bivic, A. L. The PCP pathway regulates Baz planar distribution in epithelial cells. Sci. Rep. 6, 33420 (2016).
Simões, S. et al. Rho-kinase directs Bazooka/Par-3 planar polarity during Drosophila axis elongation. Dev. Cell 19, 377–388 (2010).
Chuykin, I., Ossipova, O. & Sokol, S. Y. Par3 interacts with Prickle3 to generate apical PCP complexes in the vertebrate neural plate. eLife 7, e37881 (2018).
Schneeberger, K., Roth, S., Nieuwenhuis, E. E. S. & Middendorp, S. Intestinal epithelial cell polarity defects in disease: lessons from microvillus inclusion disease. Dis. Model. Mech. 11, dmm031088 (2018).
Wilson, P. D. Apico-basal polarity in polycystic kidney disease epithelia. Biochim. Biophys. Acta 1812, 1239–1248 (2011).
Galea, G. L. et al. Cell non-autonomy amplifies disruption of neurulation by mosaic Vangl2 deletion in mice. Nat. Commun. 12, 1159 (2021).
Kharfallah, F. et al. Scribble1 plays an important role in the pathogenesis of neural tube defects through its mediating effect of Par-3 and Vangl1/2 localization. Hum. Mol. Genet. 26, 2307–2320 (2017).
Chen, X. et al. Rare deleterious PARD3 variants in the aPKC-binding region are implicated in the pathogenesis of human cranial neural tube defects via disrupting apical tight junction formation. Hum. Mutat. 38, 378–389 (2017).
Halaoui, R. & McCaffrey, L. Rewiring cell polarity signaling in cancer. Oncogene 34, 939–950 (2015).
McCaffrey, L. M., Montalbano, J., Mihai, C. & Macara, I. G. Loss of the Par3 polarity protein promotes breast tumorigenesis and metastasis. Cancer Cell 22, 601–614 (2012).
Xue, B., Krishnamurthy, K., Allred, D. C. & Muthuswamy, S. K. Loss of Par3 promotes breast cancer metastasis by compromising cell–cell cohesion. Nat. Cell Biol. 15, 189–200 (2013).
Mescher, M. et al. The epidermal polarity protein Par3 is a non-cell autonomous suppressor of malignant melanoma. J. Exp. Med. 214, 339–358 (2017).
Halaoui, R. et al. Progressive polarity loss and luminal collapse disrupt tissue organization in carcinoma. Gene Dev. 31, 1573–1587 (2017).
Ozdamar, B. et al. Regulation of the polarity protein Par6 by TGFβ receptors controls epithelial cell plasticity. Science 307, 1603–1609 (2005).
Gunaratne, A., Thai, B. L. & Guglielmo, G. M. D. Atypical protein kinase C phosphorylates Par6 and facilitates transforming growth factor β-induced epithelial-to-mesenchymal transition. Mol. Cell. Biol. 33, 874–886 (2013).
Gunaratne, A. & Guglielmo, G. M. D. Par6 is phosphorylated by aPKC to facilitate EMT. Cell Adhes. Migr. 7, 357–361 (2013).
Burute, M. et al. Polarity reversal by centrosome repositioning primes cell scattering during epithelial-to-mesenchymal transition. Dev. Cell 40, 168–184 (2017).
Ewald, A. J. Metastasis inside-out: dissemination of cancer cell clusters with inverted polarity. EMBO J. 37, e99144 (2018).
Zajac, O. et al. Tumour spheres with inverted polarity drive the formation of peritoneal metastases in patients with hypermethylated colorectal carcinomas. Nat. Cell Biol. 20, 296–306 (2018).
Lorentzen, A. et al. Single cell polarity in liquid phase facilitates tumour metastasis. Nat. Commun. 9, 887 (2018).
Plygawko, A. T., Kan, S. & Campbell, K. Epithelial–mesenchymal plasticity: emerging parallels between tissue morphogenesis and cancer metastasis. Phil. Trans. R. Soc. B 375, 20200087 (2020).
Campbell, K. & Casanova, J. A common framework for EMT and collective cell migration. Development 143, 4291–4300 (2016).
Lüönd, F. et al. Distinct contributions of partial and full EMT to breast cancer malignancy. Dev. Cell 56, 3203–3221.e11 (2021). This study of lineage tracing of mammary tumour cells in mice demonstrates that primary tumour cells mostly undergo partial EMT, which is required for lung metastasis.
Li, Y., Zeng, B., Li, Y., Zhang, C. & Ren, G. Downregulated expression of ARHGAP10 correlates with advanced stage and high Ki-67 index in breast cancer. PeerJ 7, e7431 (2019).
Luo, N. et al. ARHGAP10, downregulated in ovarian cancer, suppresses tumorigenicity of ovarian cancer cells. Cell. Death Dis. 7, e2157 (2016).
Atashrazm, F. & Ellis, S. The polarity protein PARD3 and cancer. Oncogene 40, 4245–4262 (2021).
Acknowledgements
D.St.J. is supported by a Wellcome Trust Principal Research Fellowship and C.B. by a Wellcome Trust/Royal Society Henry Dale Fellowship.
Author information
Authors and Affiliations
Contributions
The authors contributed equally to all aspects of the article.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Peer review
Peer review information
Nature Reviews Molecular Cell Biology thanks Keith Mostov, David Bryant and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Glossary
- Basement membrane
-
A layer of extracellular matrix (ECM) between epithelia and other tissue layers.
- Epithelial–mesenchymal transition
-
(EMT). The progressive and reversible loss of epithelial characteristics such as cell–cell adhesion and apical–basal polarity to form a migratory, mesenchymal cell with front–rear polarity.
- Neural crest
-
A population of multipotent migratory cells originating from the dorsal neural tube of vertebrates. Neural crest cells give rise to diverse cell types, including peripheral nervous system cells such as cranial nerves, cartilage and bone.
- Transepithelial resistance
-
The electrical resistance across an epithelium that indicates how well the tight junctions block the passage of ions from one side of the epithelium to the other. This measures the barrier function of the epithelium.
- Follicular epithelium
-
A monolayered epithelium in Drosophila melanogaster encasing developing oocytes within the egg chambers.
- WD40 protein
-
A protein containing multiple copies of the ~40 amino acid WD40 motif. WD40 motifs fold together to form a β-propeller structure.
- MAGUK family proteins
-
Membrane-associated guanylate kinase (MAGUK) proteins are scaffolding proteins defined by the presence of an SH3 domain, one or more PDZ domains and a catalytically inactive guanylate kinase (GUK) domain.
- RAS association domain-containing proteins
-
A family of proteins that contain an N-terminal Ras association domain with a ubiquitin-like fold that mediates protein–protein interactions, although not necessarily with Ras.
- Planar cell polarity
-
(PCP). A polarity axis that aligns cells and cellular structures in the plane of the epithelium, perpendicular to the apical–basal axis.
- Moesin
-
The sole member of the Ezrin, Moesin, Radixin (ERM) family of proteins in Drosophila. ERM proteins link the plasma membrane and transmembrane proteins to the cortical actin cytoskeleton.
- Spectrin
-
α-Spectrins and β-spectrins form rod-like heterotetramers that bind actin and the plasma membrane to form a hexagonal cytoskeletal scaffold that supports the plasma membrane. In insects, α-spectrin and βH-spectrin tetramers form the spectrin cytoskeleton beneath the apical plasma membrane, whereas α-spectrin and β-spectrin tetramers underlie the basolateral membrane.
- Hippo pathway
-
A signalling pathway in epithelia that regulates cell division and promotes apoptosis, therefore controlling tissue growth.
- α-Catenin
-
A component of the E-cadherin adhesion complex that links the actin cytoskeleton to E-cadherin through β-catenin.
- Katanin
-
A microtubule-severing protein that is a component of non-centrosomal microtubule organizing centres.
- WDR62
-
A protein that localizes to non-centrosomal microtubule organizing centres and spindle poles.
- Blastoderm
-
An early stage in insect development when the embryo is composed of a single layer of nuclei or cells surrounding a central yolk mass.
- Floorplate
-
Neuroepithelial tissue that lines the medio-ventral part of the neural tube and that constitutes an important signalling domain in dorsal–ventral patterning of the spinal cord.
- Intraflagellar transport
-
Bidirectional transport of particles between the cilia tip and the cell body. Important for assembly and maintenance of cilia.
- Exocyst
-
A protein complex that tethers vesicles to the plasma membrane prior to fusion.
- SNARE complexes
-
Transient protein complexes formed by v-SNARES on exocytic vesicles and t-SNARES in the plasma membrane that drives vesicle fusion.
- Glycosphingolipids
-
A class of glycosylated lipids that are enriched in the outer leaflet of the plasma membrane.
- Apical membrane initiation site
-
(AMIS). A term initially coined in mammalian epithelial cysts in 3D culture. The AMIS is a transient structure, marked by scaffolding and junctional proteins such as PAR-3, ZO-1 and cingulin, that marks the site where apical vesicles will fuse to begin forming the apical domain.
- Midbody
-
A tubulin-rich structure present at the midpoint between dividing cells just before abscission.
- Amnioserosa
-
An extra-embryonic tissue that covers the dorsal side of the developing Drosophila melanogaster embryo.
- Snail
-
A zinc-finger transcription factor that acts to repress expression of genes, including cadherin-encoding genes, which is known for its role in mediating epithelial–mesenchymal transition (EMT).
- Radial glial cells
-
Progenitor cells within the vertebrate central nervous system with long radial processes that guide radial migration of newborn neurons.
- Sensory organ precursors
-
Progenitor cells in the Drosophila melanogaster peripheral nervous system that divide asymmetrically within the plane of the epithelium and give rise to the sensory bristles.
- Germ band extension
-
A process that elongates the body axis of early Drosophila melanogaster embryos, whereby the epithelial tissue simultaneously converges along the dorsal–ventral axis and extends along the anterior–posterior axis.
- Convergence–extension
-
The extension of tissue in one axis and narrowing in the orthogonal axis, driven by both cell migration and cell intercalation. Important for body axis elongation.
- Microvillus inclusion disease
-
A rare genetic disorder causing severe diarrhoea and defects in nutrient absorption that is characterized by the loss of the apical brush border in intestinal enterocytes and the presence of intracellular inclusions containing microvilli.
- TGFβ
-
A cytokine that has wide-ranging effects, including on cell growth, differentiation and apoptosis, and promotes epithelial–mesenchymal transition (EMT).
- SMAD
-
A group of transcription factors serving as the main transducers of TGFβ signalling.
- Ezrin
-
An ezrin, moesin, radixin (ERM) protein that links the plasma membrane to the cortical actin cytoskeleton.
Rights and permissions
About this article
Cite this article
Buckley, C.E., St Johnston, D. Apical–basal polarity and the control of epithelial form and function. Nat Rev Mol Cell Biol 23, 559–577 (2022). https://doi.org/10.1038/s41580-022-00465-y
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41580-022-00465-y