Interplay between actomyosin and E-cadherin dynamics regulates cell shape in the Drosophila embryonic epidermis

Abstract

Precise regulation of cell shape is vital for building functional tissues. Here, we study the mechanisms that lead to the formation of highly elongated anisotropic epithelial cells in the Drosophila epidermis. We demonstrate that this cell shape is the result of two counteracting mechanisms at the cell surface that regulate the degree of elongation: actomyosin, which inhibits cell elongation downstream of RhoA (Rho1 in Drosophila) and intercellular adhesion, modulated via clathrin-mediated endocytosis of E-cadherin (encoded by shotgun in flies), which promotes cell elongation downstream of the GTPase Arf1 (Arf79F in Drosophila). We show that these two mechanisms do not act independently but are interconnected, with RhoA signalling reducing Arf1 recruitment to the plasma membrane. Additionally, cell adhesion itself regulates both mechanisms – p120-catenin, a regulator of intercellular adhesion, promotes the activity of both Arf1 and RhoA. Altogether, we uncover a complex network of interactions between cell–cell adhesion, the endocytic machinery and the actomyosin cortex, and demonstrate how this network regulates cell shape in an epithelial tissue in vivo.

Interactions and Feedbacks in E-Cadherin Transcriptional Regulation

“…The strength of adhesion correlates with the number of E-cad molecules on cell surfaces ( Chu et al, 2004 ). Consequently, the regulation of E-cad surface levels in epithelia is instrumental in many processes, and even mild changes in E-cad levels profoundly affect many processes such as cell rearrangements, proliferation, and tissue architecture ( Ciesiolka et al, 2004 ; Lecuit and Yap, 2015 ; Mohan et al, 2018 ; Greig and Bulgakova, 2020 ). Multiple mechanisms regulate E-cad surface levels including intracellular trafficking, transcriptional regulation, post-translational modifications, and protein degradation ( Palacios et al, 2005 ; Bertocchi et al, 2012 ; Serrano-Gomez et al, 2016 ; Brüser and Bogdan, 2017 ; Cai et al, 2018 ).…”

Multifaceted control of E-cadherin dynamics by the Adaptor Protein Complex 1 during epithelial morphogenesis

“…We examined if inhibiting E-cad endocytosis ameliorated the phenotype, which we observed upon AP-1 knockdown. To specifically block endocytosis of E-cad without effects on general endocytic machinery, we overexpressed p120-catenin, which directly binds the E-cad intracellular domain and prevents its internalization in both flies and mammalian cells [59,64,65]. While overexpression of p120-catenin did not affect wing size by itself, co- However, there was less cell death visualised using Dcp-1 antibody in wing discs that overexpressed p120-catenin than in those that did not upon AP-1µ knockdown (Fig 8D , E).…”

“…Additionally, both Arf1 and Arf6 -two small GTPases, which contributed to the recruitment of AP-1A and AP-1B, respectively, in mammalian cells -are found at the plasma membrane, where they regulate endocytosis in both fly and mammalian cells [31,65,[68][69][70][71][72]. Moreover, Arf1 and AP-1 share the localization pattern being present at both TGN and AJs.…”

The Cross-Talk Between EGFR and E-Cadherin

“…In colon adenocarcinoma cells, phosphorylation of Tyr228 correlates with better prognosis and inhibits cell invasion ( Ding et al, 2019 ), whereas in the breast cancer cells MDA-MB-231 it is essential for the invasiveness-promoting activity of p120-catenin isoform 1 ( Yanagisawa et al, 2008 ; Kourtidis et al, 2015 ). In either case, the changes in RhoA activity are likely to alter (promote or inhibit) E-cadherin endocytosis depending on the context ( Lee and Harris, 2013 ; Kourtidis et al, 2015 ; Greig and Bulgakova, 2020 ).…”