Role of the adhesion molecule Sidekick in adherens junction remodeling during developmental morphogenesis
Supervisor:Dr. Benedicte Sanson
Second Supervisors DepartmentWellcome Trust Sanger Institute
We have identified the adhesion molecule Sidekick, which was known for its role in synaptogenesis in the visual system, as the first component of tricellular adherens junctions (tAJs) in developing epithelia (1, 2). Epithelia change shape extensively during embryo development and this requires the remodeling of the contacts between cells, which include adherens and occluding junctions. Whereas there is knowledge about how bicellular contacts are remodeled, less is known about tricellular contacts, the “cell corners”. Cell behaviours important to shape tissues such as polarised cell intercalation, cell division and cell extrusion require the remodelling of cell-cell contacts, posing a conformational problem at tricellular junctions that has started to be addressed. Also there is evidence that tricellular vertices are important for tension sensing and force transmission during epithelial remodelling. Until recently, resident proteins at tricellular contacts were known only for occluding junctions, both in vertebrates (angulins and tricellulins) and in invertebrates (Gliotactin, Anakonda, M6) (3). The identification of Sidekick gives an opportunity to study the role of tricellular adherens junctions. Recent studies, including from our group, show that Sidekick facilitates polarized cell intercalation in four different tissues in Drosophila (2,4,5). The goal of this PhD project is to follow-up on these findings and investigate the mechanisms by which Sidekick contributes to junctional remodeling, using the early Drosophila embryo as a model. Approaches will include super-resolution live microscopy to follow Sdk localization during remodeling, photoactivation techniques to ask how adherens junction components and the actomyosin cytoskeleton are redistributed around tAJs, molecular and cellular approaches to elucidate a pathway that localizes Sdk at cell corners.
1) Lye, C. M., Naylor, H. W. and Sanson, B. (2014). Subcellular localisations of the CPTI collection of YFP-tagged proteins in Drosophila embryos. Development 141, 4006-4017.
2)T.Finegan*, N. Hervieux*, A. NestorBergmann, A. Fletcher, G. Blanchard, B. Sanson (2019). The tricellular vertex-specific adhesion molecule Sidekick facilitates polarised cell intercalation during Drosophila axis extension. BioRxiv 704932; https://doi.org/10.1101/704932 (under revision at PloS Biology)
3) Higashi T, Miller AL. Tricellular junctions: how to build junctions at the TRICkiest points of epithelial cells. Molecular Biology of the Cell. 2017;28(15):2023-34. doi: 10.1091/mbc.E16-10-0697.
4) Letizia, A., He, D., Astigarraga, S., Colombelli, J., Hatini, V., Llimargas, M. and Treisman, J. E. (2019). Sidekick Is a Key Component of Tricellular Adherens Junctions that Acts to Resolve Cell Rearrangements. Dev Cell 50, 313-326 e315.
5) Uechi, H. and Kuranaga, E. (2019). The Tricellular Junction Protein Sidekick Regulates Vertex Dynamics to Promote Bicellular Junction Extension. Dev Cell 50, 327-338 e325.
Drosophila Sidekick has two vertebrate homologues, Sdk-1 and Sdk-2, which regulate lamina-specific connectivity during retinal development (6). Besides their neuronal functions, Sdks have been implicated in podocyte function in the kidney (7). This is where the tricellular junctional localisation we have identified for Drosophila Sdk might be particularly relevant. Our first step will be to investigate if Sdks localise at tricellular contacts in vertebrates as in Drosophila. Independently of the molecular identity of resident proteins, our work in tAJs remodelling in the Drosophila model will shed light on general principles of epithelial morphogenesis, which is relevant to health.
6) Yamagata M, Weiner JA, Sanes JR. Sidekicks: synaptic adhesion molecules that promote lamina-specific connectivity in the retina. Cell. 2002;110(5):649-60. Epub 2002/09/17. doi: 10.1016/s0092-8674.
7) Kaufman L, Potla U, Coleman S, Dikiy S, Hata Y, Kurihara H, et al. Up-regulation of the homophilic adhesion molecule sidekick-1 in podocytes contributes to glomerulosclerosis. J Biol Chem. 2010;285(33):25677-85. Epub 2010/06/22. doi: 10.1074/jbc.M110.133959.