Abstract
The integrity of polarized epithelia is critical for development and human health. Many questions remain concerning the full complement and the function of the proteins that regulate cell polarity1. Here we report that the Drosophila FERM proteins Yurt (Yrt)2 and Coracle (Cora)3 and the membrane proteins Neurexin IV (Nrx-IV)4 and Na+,K+-ATPase5 are a new group of functionally cooperating epithelial polarity proteins. This ‘Yrt/Cora group’ promotes basolateral membrane stability and shows negative regulatory interactions with the apical determinant Crumbs (Crb). Genetic analyses indicate that Nrx-IV and Na+,K+-ATPase act together with Cora in one pathway, whereas Yrt acts in a second redundant pathway. Moreover, we show that the Yrt/Cora group is essential for epithelial polarity during organogenesis but not when epithelial polarity is first established or during terminal differentiation. This property of Yrt/Cora group proteins explains the recovery of polarity in embryos lacking the function of the Lethal giant larvae (Lgl) group of basolateral polarity proteins6,7. We also find that the mammalian Yrt orthologue EPB41L5 (also known as YMO1 and Limulus)8,9,10 is required for lateral membrane formation, indicating a conserved function of Yrt proteins in epithelial polarity.
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References
Nelson, W. J. Adaptation of core mechanisms to generate cell polarity. Nature 422, 766–774 (2003)
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)
Fehon, R. G., Dawson, I. A. & Artavanis-Tsakonas, S. A Drosophila homologue of membrane-skeleton protein 4.1 is associated with septate junctions and is encoded by the coracle gene. Development 120, 545–557 (1994)
Baumgartner, S. et al. A Drosophila neurexin is required for septate junction and blood-nerve barrier formation and function. Cell 87, 1059–1068 (1996)
Paul, S. M., Ternet, M., Salvaterra, P. M. & Beitel, G. J. The Na+/K+ ATPase is required for septate junction function and epithelial tube-size control in the Drosophila tracheal system. Development 130, 4963–4974 (2003)
Tanentzapf, G. & Tepass, U. Interactions between the crumbs, lethal giant larvae and bazooka pathways in epithelial polarization. Nature Cell Biol. 5, 46–52 (2003)
Bilder, D., Schober, M. & Perrimon, N. Integrated activity of PDZ protein complexes regulates epithelial polarity. Nature Cell Biol. 5, 53–58 (2003)
Lee, J. D., Silva-Gagliardi, N. F., Tepass, U., McGlade, C. J. & Anderson, K. V. The FERM protein Epb4.1l5 is required for organization of the neural plate and for the epithelial–mesenchymal transition at the primitive streak of the mouse embryo. Development 134, 2007–2016 (2007)
Gosens, I. et al. FERM protein EPB41L5 is a novel member of the mammalian CRB–MPP5 polarity complex. Exp. Cell Res. 313, 3959–3970 (2007)
Hirano, M., Hashimoto, S., Yonemura, S., Sabe, H. & Aizawa, S. EPB41L5 functions to post-transcriptionally regulate cadherin and integrin during epithelial–mesenchymal transition. J. Cell Biol. 182, 1217–1230 (2008)
Hsu, Y. C., Willoughby, J. J., Christensen, A. K. & Jensen, A. M. Mosaic Eyes is a novel component of the Crumbs complex and negatively regulates photoreceptor apical size. Development 133, 4849–4859 (2006)
Wodarz, A., Hinz, U., Engelbert, M. & Knust, E. Expression of crumbs confers apical character on plasma membrane domains of ectodermal epithelia of Drosophila . Cell 82, 67–76 (1995)
Tepass, U., Tanentzapf, G., Ward, R. & Fehon, R. Epithelial cell polarity and cell junctions in Drosophila . Annu. Rev. Genet. 35, 747–784 (2001)
Pellikka, M. et al. Crumbs, the Drosophila homologue of human CRB1/RP12, is essential for photoreceptor morphogenesis. Nature 416, 143–149 (2002)
Wu, V. M. & Beitel, G. J. A junctional problem of apical proportions: epithelial tube-size control by septate junctions in the Drosophila tracheal system. Curr. Opin. Cell Biol. 16, 493–499 (2004)
Tepass, U. & Hartenstein, V. The development of cellular junctions in the Drosophila embryo. Dev. Biol. 161, 563–596 (1994)
Genova, J. L. & Fehon, R. G. Neuroglian, Gliotactin, and the Na+/K+ ATPase are essential for septate junction function in Drosophila . J. Cell Biol. 161, 979–989 (2003)
Lamb, R. S., Ward, R. E., Schweizer, L. & Fehon, R. G. Drosophila coracle, a member of the protein 4.1 superfamily, has essential structural functions in the septate junctions and developmental functions in embryonic and adult epithelial cells. Mol. Biol. Cell 9, 3505–3519 (1998)
Bilder, D., Li, M. & Perrimon, N. Cooperative regulation of cell polarity and growth by Drosophila tumor suppressors. Science 289, 113–116 (2000)
Wu, V. M. et al. Drosophila Varicose, a member of a new subgroup of basolateral MAGUKs, is required for septate junctions and tracheal morphogenesis. Development 134, 999–1009 (2007)
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)
Yamanaka, T. et al. Mammalian Lgl forms a protein complex with PAR-6 and aPKC independently of PAR-3 to regulate epithelial cell polarity. Curr. Biol. 13, 734–743 (2003)
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)
Harris, T. J. & Peifer, M. Adherens junction-dependent and -independent steps in the establishment of epithelial cell polarity in Drosophila . J. Cell Biol. 167, 135–147 (2004)
Mavrakis, M., Rikhy, R. & Lippincott-Schwartz, J. Plasma membrane polarity and compartmentalization are established before cellularization in the fly embryo. Dev. Cell 16, 93–104 (2009)
Jensen, A. M. & Westerfield, M. Zebrafish mosaic eyes is a novel FERM protein required for retinal lamination and retinal pigmented epithelial tight junction formation. Curr. Biol. 14, 711–717 (2004)
Gassama-Diagne, A. et al. Phosphatidylinositol-3,4,5-trisphosphate regulates the formation of the basolateral plasma membrane in epithelial cells. Nature Cell Biol. 8, 963–970 (2006)
Kizhatil, K. et al. Ankyrin-G and 2-spectrin collaborate in biogenesis of lateral membrane of human bronchial epithelial cells. J. Biol. Chem. 282, 2029–2037 (2007)
Hortsch, M. & Margolis, B. Septate and paranodal junctions: kissing cousins. Trends Cell Biol. 13, 557–561 (2003)
Bennett, V. & Healy, J. Organizing the fluid membrane bilayer: diseases linked to spectrin and ankyrin. Trends Mol. Med. 14, 28–36 (2008)
Hoover, K. B. & Bryant, P. J. Drosophila Yurt is a new protein-4.1-like protein required for epithelial morphogenesis. Dev. Genes Evol. 212, 230–238 (2002)
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)
Palladino, M. J., Bower, J. E., Kreber, R. & Ganetzky, B. Neural dysfunction and neurodegeneration in Drosophila Na+/K+ ATPase alpha subunit mutants. J. Neurosci. 23, 1276–1286 (2003)
Bieber, A. J. et al. Drosophila neuroglian: a member of the immunoglobulin superfamily with extensive homology to the vertebrate neural adhesion molecule L1. Cell 59, 447–460 (1989)
Auld, V. J., Fetter, R. D., Broadie, K. & Goodman, C. S. Gliotactin, a novel transmembrane protein on peripheral glia, is required to form the blood-nerve barrier in Drosophila . Cell 81, 757–767 (1995)
Grenningloh, G., Rehm, E. J. & Goodman, C. S. Genetic analysis of growth cone guidance in drosophila: Fasciclin II functions as a neuronal recognition molecule. Cell 67, 45–57 (1991)
Whitlock, K. Development of Drosophila wing sensory neurons in mutants with missing or modified cell surface molecules. Development 117, 1251–1260 (1993)
Beitel, G. J. & Krasnow, M. A. Genetic control of epithelial tube size in the Drosophila tracheal system. Development 127, 3271–3282 (2000)
Faivre-Sarrailh, C. et al. Drosophila contactin, a homolog of vertebrate contactin, is required for septate junction organization and paracellular barrier function. Development 131, 4931–4942 (2004)
Llimargas, M., Strigini, M., Katidou, M., Karagogeos, D. & Casanova, J. Lachesin is a component of a septate junction-based mechanism that controls tube size and epithelial integrity in the Drosophila tracheal system. Development 131, 181–190 (2004)
Chou, T. B. & Perrimon, N. The autosomal Flp–Dfs technique for generating germline mosaics in Drosophila melanogaster . Genetics 144, 1673–1679 (1996)
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)
Paul, S. M., Palladino, M. J. & Beitel, G. J. A pump-independent function of the Na,K-ATPase is required for epithelial junction function and tracheal tube-size control. Development 134, 147–155 (2007)
Groth, A. C., Fish, M., Nusse, R. & Calos, M. P. Construction of transgenic Drosophila by using the site-specific integrase from phage C31. Genetics 166, 1775–1782 (2004)
Laprise, P. et al. Phosphatidylinositol 3-kinase controls human intestinal epithelial cell differentiation by promoting adherens junction assembly and p38 MAPK activation. J. Biol. Chem. 277, 8226–8234 (2002)
Hortsch, M., Wang, Y. M., Marikar, Y. & Bieber, A. J. The cytoplasmic domain of the Drosophila cell adhesion molecule neuroglian is not essential for its homophilic adhesive properties in S2 cells. J. Biol. Chem. 270, 18809–18817 (1995)
Acknowledgements
We would like to thank V. Auld, J. Casanova, H. Bellen, M. Hortsch, R. Fehon, M. Bhat, R. Schuh, the Developmental Studies Hybridoma Bank and the Bloomington Drosophila Stock Center for reagents. We thank D. Godt, R. Winklbauer and T. Harris for critical comments on the manuscript, and H. Hong, M. Pellikka and W. Russin for technical assistance. This work was supported by postdoctoral fellowships from the CIHR (to P.L.), a predoctoral fellowship from the Vision Science Research Program, University of Toronto (to S.B.) and by NIH Lung Biology Training Grant 5 (to S.M.P.). Operating support was provided by the CIHR (to U.T. and P.L.), the Foundation Fighting Blindness Canada (to C.J.M.) and the NIH (to G.J.B.).
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Laprise, P., Lau, K., Harris, K. et al. Yurt, Coracle, Neurexin IV and the Na+,K+-ATPase form a novel group of epithelial polarity proteins. Nature 459, 1141–1145 (2009). https://doi.org/10.1038/nature08067
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DOI: https://doi.org/10.1038/nature08067
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