Editing Invagination (section)

== Cellular mechanisms ==
Invagination can be driven by a number of mechanisms at the cellular level. Regardless of the force-generating mechanism that causes the bending of the [[epithelium]], most instances of invagination result in a stereotypical cell shape change. At the side of the epithelium exposed to the environment (the apical side), the surface of cells shrinks, and at the side of the cell in contact with the [[basement membrane]] (the basal side), the cell surfaces expand. Thus, cells become wedge-shaped. As these cells change shape, the tissue bends in the direction of the apical surface. In many–– though not all––cases, this process involves active constriction of the apical surface by the [[actin]]-[[myosin]] [[cytoskeleton]]. Furthermore, while most invagination processes involve shrinking of the apical surface, there have been cases observed where the opposite happens - the basal surface constricts and the apical surface expands, such as in [[Optic cup (embryology)|optic cup]] morphogenesis and formation of the [[midbrain-hindbrain boundary]] in [[zebrafish]].<ref>Tozluoǧlu, Melda, and Yanlan Mao. 2020. “On Folding Morphogenesis, a Mechanical Problem.” ''Philosophical Transactions of the Royal Society B: Biological Sciences'' 375 (1809): 20190564. <nowiki>https://doi.org/10.1098/rstb.2019.0564</nowiki>.</ref><ref>Sidhaye, Jaydeep, and Caren Norden. 2017. “Concerted Action of Neuroepithelial Basal Shrinkage and Active Epithelial Migration Ensures Efficient Optic Cup Morphogenesis.” Edited by Didier YR Stainier. ''eLife'' 6 (April):e22689. <nowiki>https://doi.org/10.7554/eLife.22689</nowiki>.</ref><ref>Gutzman, Jennifer H., Ellie G. Graeden, Laura Anne Lowery, Heidi S. Holley, and Hazel Sive. 2008. “Formation of the Zebrafish Midbrain–Hindbrain Boundary Constriction Requires Laminin-Dependent Basal Constriction.” ''Mechanisms of Development'' 125 (11): 974–83. <nowiki>https://doi.org/10.1016/j.mod.2008.07.004</nowiki>.</ref>

=== Apical constriction ===
{{main|Apical constriction}}
[[File:Invagination_by_apical_constriction.jpg|thumb|459x459px|Apical constriction leading to invagination of a monolayer of cells]]
Apical constriction is an active process that results in the shrinkage of the apical side of the cell. This causes the cell shape to change from a column or cube-shaped cell to become wedge-shaped. Apical constriction is powered by the activity of the proteins [[actin]] and [[myosin]] interacting in a complex network known as the actin-myosin cytoskeleton. Myosin, a motor protein, generates force by pulling filaments of actin together. Myosin activity is regulated by the [[phosphorylation]] of one of its [[Protein subunit|subunits]], [[Myosin light chain|myosin regulatory light chain]]. Thus, kinases such as [[Rho-associated coiled-coil kinase]] (ROCK), which phosphorylate myosin, as well as [[Phosphatase|phosphatases]], which [[Dephosphorylation|dephosphorylate]] myosin, are regulators of actomyosin contraction in cells.<ref name=":1">Martin, Adam C., and Bob Goldstein. 2014. “Apical Constriction: Themes and Variations on a Cellular Mechanism Driving Morphogenesis.” ''Development'' 141 (10): 1987–98. <nowiki>https://doi.org/10.1242/dev.102228</nowiki>.</ref>

The arrangement of actin and myosin in the [[cell cortex]] and the way they generate force can vary across contexts. Classical models of apical constriction in embryos and epithelia in [[cell culture]] showed that actin-myosin bundles are assembled around the circumference of the cell in association with [[Adherens junction|adherens junctions]] between cells. Contraction of the actin-myosin bundles thus results in a constriction of the apical surface in a process that has been likened to the tightening of a purse string.<ref name=":1" /> More recently, in the context of a cultured epithelium derived from the mouse [[organ of Corti]], it has also been shown that the arrangement of the actin and myosin around the cell circumerence is similar to a muscle [[sarcomere]], where there are a repeating units of myosin connected to antiparallel actin bundles.<ref name=":2">Ebrahim, Seham, Tomoki Fujita, Bryan A. Millis, Elliott Kozin, Xuefei Ma, Sachiyo Kawamoto, Michelle A. Baird, et al. 2013. “NMII Forms a Contractile Transcellular Sarcomeric Network to Regulate Apical Cell Junctions and Tissue Geometry.” ''Current Biology'' 23 (8): 731–36. <nowiki>https://doi.org/10.1016/j.cub.2013.03.039</nowiki>.</ref> In other cells, a network of myosin and actin in the middle of the apical surface can also generate apical constriction. For example, in cells of the ''Drosophila'' ventral furrow, the organization of actin and myosin is analogous to a muscle sarcomere arranged radially.<ref>Heer, Natalie C., and Adam C. Martin. 2017. “Tension, Contraction and Tissue Morphogenesis.” ''Development'' 144 (23): 4249–60. <nowiki>https://doi.org/10.1242/dev.151282</nowiki>.</ref><ref name=":3">Coravos, Jonathan S., and Adam C. Martin. 2016. “Apical Sarcomere-like Actomyosin Contracts Nonmuscle ''Drosophila'' Epithelial Cells.” ''Developmental Cell'' 39 (3): 346–58. <nowiki>https://doi.org/10.1016/j.devcel.2016.09.023</nowiki>.</ref> In some contexts, a less clearly organized “cortical flow” of actin and myosin can also generate contraction of the apical surface.<ref name=":2" />

=== Basal relaxation ===
To maintain a constant cell volume during apical constriction, cells must either change their height or expand the basal surface of their cells. While the process of basal relaxation has been less thoroughly studied, in some cases it has been directly observed that the process of apical constriction occurs alongside an active disassembly of the actin-myosin network at the basal surface of the cell, allowing the basal side of the cell to expand. For example, this has been observed in the ''Drosophila'' ventral furrow invagination<ref>Polyakov, Oleg, Bing He, Michael Swan, Joshua W. Shaevitz, Matthias Kaschube, and Eric Wieschaus. 2014. “Passive Mechanical Forces Control Cell-Shape Change during Drosophila Ventral Furrow Formation.” ''Biophysical Journal'' 107 (4): 998–1010. <nowiki>https://doi.org/10.1016/j.bpj.2014.07.013</nowiki>.</ref><ref name=":4">Pearl, Esther J., Jingjing Li, and Jeremy B. A. Green. 2017. “Cellular Systems for Epithelial Invagination.” ''Philosophical Transactions of the Royal Society B: Biological Sciences'' 372 (1720): 20150526. <nowiki>https://doi.org/10.1098/rstb.2015.0526</nowiki>.</ref> and the formation of the [[otic placode]] in the chicken.<ref>Sai, XiaoRei, and Raj K. Ladher. 2008. “FGF Signaling Regulates Cytoskeletal Remodeling during Epithelial Morphogenesis.” ''Current Biology'' 18 (13): 976–81. <nowiki>https://doi.org/10.1016/j.cub.2008.05.049</nowiki>.</ref><ref>Sai, Xiaorei, and Raj K. Ladher. 2015. “Early Steps in Inner Ear Development: Induction and Morphogenesis of the Otic Placode.” ''Frontiers in Pharmacology'' 6 (February). <nowiki>https://doi.org/10.3389/fphar.2015.00019</nowiki>.</ref>

=== Changes in cell height ===
Invagination also often involves, and can be driven by, changes in cell height. When apical constriction occurs, this can lead to elongation of cells to maintain constant cell volume, and consequently a thickening of the epithelium. However, shortening of cells along the apical-basal axis can also help deepen the pit formed during invagination.<ref>Kondo, Takefumi, and Shigeo Hayashi. 2015. “Mechanisms of Cell Height Changes That Mediate Epithelial Invagination.” ''DGD'' 57 (4): 313–23. <nowiki>https://doi.org/10.1111/dgd.12224</nowiki>.</ref> Active changes in cell shape to cause cell shortening have been shown to contribute to invagination in a few cases. For example, in the ''Drosophila'' leg epithelium, [[Apoptosis|apoptotic]] cells shrink and pull on the apical surface of the epithelium via an apical-basal cable made up of actin and myosin.<ref>Monier, Bruno, Melanie Gettings, Guillaume Gay, Thomas Mangeat, Sonia Schott, Ana Guarner, and Magali Suzanne. 2015. “Apico-Basal Forces Exerted by Apoptotic Cells Drive Epithelium Folding.” ''Nature'' 518 (7538): 245–48. <nowiki>https://doi.org/10.1038/nature14152</nowiki>.</ref> In the invagination that occurs in [[Ascidiacea|ascidian]] gastrulation, cells first undergo apical constriction and then change their shape to become rounder ––and thus shorter along the apical-basal axis––which is responsible for the completion of the invagination movement.<ref>Sherrard, Kristin, François Robin, Patrick Lemaire, and Edwin Munro. 2010. “Sequential Activation of Apical and Basolateral Contractility Drives Ascidian Endoderm Invagination.” ''Current Biology'' 20 (17): 1499–1510. <nowiki>https://doi.org/10.1016/j.cub.2010.06.075</nowiki>.</ref> During [[cell division]], cells also naturally take on a rounded morphology. The rapid drop in cell height caused by rounding of cells during mitosis has also been implicated in invagination of the ''Drosophila'' [[Trachea|tracheal]] placode.<ref>Kondo, Takefumi, and Shigeo Hayashi. 2013. “Mitotic Cell Rounding Accelerates Epithelial Invagination.” ''Nature'' 494 (7435): 125–29. <nowiki>https://doi.org/10.1038/nature11792</nowiki>.</ref>

=== Supracellular cables ===
Supracellular actomyosin cables are structures of actin and myosin that align between cells next to each other and are connected by cell junctions.<ref name=":4" /> These cables play many roles in morphogenesis during embryonic development, including invagination.<ref name=":5">Röper, Katja. 2013. “Supracellular Actomyosin Assemblies during Development.” BioArchitecture 3 (2): 45–49. <nowiki>https://doi.org/10.4161/bioa.25339</nowiki>.</ref> Rather than solely relying on apical constriction of individual cells, invagination can be driven by compressive forces from this cable contracting around the site of invagination, such as in the case of [[salivary gland]] invagination in ''Drosophila''.<ref>Röper, Katja. 2012. “Anisotropy of Crumbs and aPKC Drives Myosin Cable Assembly during Tube Formation.” ''Developmental Cell'' 23 (5): 939–53. <nowiki>https://doi.org/10.1016/j.devcel.2012.09.013</nowiki>.</ref><ref>Chung, SeYeon, Sangjoon Kim, and Deborah J Andrew. 2017. “Uncoupling Apical Constriction from Tissue Invagination.” Edited by Hugo J Bellen. ''eLife'' 6 (March):e22235. <nowiki>https://doi.org/10.7554/eLife.22235</nowiki>.</ref> In neural tube formation in the chick embryo, rows of supracellular cables stretching across the site of invagination help pull the tissue together to facilitate bending into a tube.<ref name=":5" /><ref>Nishimura, Tamako, Hisao Honda, and Masatoshi Takeichi. 2012. “Planar Cell Polarity Links Axes of Spatial Dynamics in Neural-Tube Closure.” ''Cell'' 149 (5): 1084–97. <nowiki>https://doi.org/10.1016/j.cell.2012.04.021</nowiki>.</ref><ref>Nishimura, Tamako, and Masatoshi Takeichi. 2008. “Shroom3-Mediated Recruitment of Rho Kinases to the Apical Cell Junctions Regulates Epithelial and Neuroepithelial Planar Remodeling.” ''Development'' 135 (8): 1493–1502. <nowiki>https://doi.org/10.1242/dev.019646</nowiki>.</ref>