Journal articles: 'Lumen Morphogenesis'

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Herrema, Hilde, Dominika Czajkowska, Delphine Théard, Johanna M. van der Wouden, Dharamdajal Kalicharan, Behnam Zolghadr, Dick Hoekstra, and Sven C. D. van IJzendoorn. "Rho Kinase, Myosin-II, and p42/44 MAPK Control Extracellular Matrix-mediated Apical Bile Canalicular Lumen Morphogenesis in HepG2 Cells." Molecular Biology of the Cell 17, no. 7 (July 2006): 3291–303. http://dx.doi.org/10.1091/mbc.e06-01-0067.

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The molecular mechanisms that regulate multicellular architecture and the development of extended apical bile canalicular lumens in hepatocytes are poorly understood. Here, we show that hepatic HepG2 cells cultured on glass coverslips first develop intercellular apical lumens typically formed by a pair of cells. Prolonged cell culture results in extensive organizational changes, including cell clustering, multilayering, and apical lumen morphogenesis. The latter includes the development of large acinar structures and subsequent elongated canalicular lumens that span multiple cells. These morphological changes closely resemble the early organizational pattern during development, regeneration, and neoplasia of the liver and are rapidly induced when cells are cultured on predeposited extracellular matrix (ECM). Inhibition of Rho kinase or its target myosin-II ATPase in cells cultured on glass coverslips mimics the morphogenic response to ECM. Consistently, stimulation of Rho kinase and subsequent myosin-II ATPase activity by lipoxygenase-controlled eicosatetranoic acid metabolism inhibits ECM-mediated cell multilayering and apical lumen morphogenesis but not initial apical lumen formation. Furthermore, apical lumen remodeling but not cell multilayering requires basal p42/44 MAPK activity. Together, the data suggest a role for hepatocyte-derived ECM in the spatial organization of hepatocytes and apical lumen morphogenesis and identify Rho kinase, myosin-II, and MAPK as potentially important players in different aspects of bile canalicular lumen morphogenesis.

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Datta, Anirban, David M. Bryant, and Keith E. Mostov. "Molecular Regulation of Lumen Morphogenesis." Current Biology 21, no. 3 (February 2011): R126—R136. http://dx.doi.org/10.1016/j.cub.2010.12.003.

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Enemchukwu, Nduka O., Ricardo Cruz-Acuña, Tom Bongiorno, Christopher T. Johnson, José R. García, Todd Sulchek, and Andrés J. García. "Synthetic matrices reveal contributions of ECM biophysical and biochemical properties to epithelial morphogenesis." Journal of Cell Biology 212, no. 1 (December 28, 2015): 113–24. http://dx.doi.org/10.1083/jcb.201506055.

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Epithelial cells cultured within collagen and laminin gels proliferate to form hollow and polarized spherical structures, recapitulating the formation of a rudimentary epithelial organ. However, the contributions of extracellular matrix (ECM) biochemical and biophysical properties to morphogenesis are poorly understood because of uncontrolled presentation of multiple adhesive ligands, limited control over mechanical properties, and lot-to-lot compositional variability in these natural ECMs. We engineered synthetic ECM-mimetic hydrogels with independent control over adhesive ligand density, mechanical properties, and proteolytic degradation to study the impact of ECM properties on epithelial morphogenesis. Normal cyst growth, polarization, and lumen formation were restricted to a narrow range of ECM elasticity, whereas abnormal morphogenesis was observed at lower and higher elastic moduli. Adhesive ligand density dramatically regulated apicobasal polarity and lumenogenesis independently of cell proliferation. Finally, a threshold level of ECM protease degradability was required for apicobasal polarity and lumen formation. This synthetic ECM technology provides new insights into how cells transduce ECM properties into complex morphogenetic behaviors.

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Chaki, Sankar P., Rola Barhoumi, and Gonzalo M. Rivera. "Actin remodeling by Nck regulates endothelial lumen formation." Molecular Biology of the Cell 26, no. 17 (September 2015): 3047–60. http://dx.doi.org/10.1091/mbc.e15-06-0338.

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Multiple angiogenic cues modulate phosphotyrosine signaling to promote vasculogenesis and angiogenesis. Despite its functional and clinical importance, how vascular cells integrate phosphotyrosine-dependent signaling to elicit cytoskeletal changes required for endothelial morphogenesis remains poorly understood. The family of Nck adaptors couples phosphotyrosine signals with actin dynamics and therefore is well positioned to orchestrate cellular processes required in vascular formation and remodeling. Culture of endothelial cells in three-dimensional collagen matrices in the presence of VEGF stimulation was combined with molecular genetics, optical imaging, and biochemistry to show that Nck-dependent actin remodeling promotes endothelial cell elongation and proper organization of VE-cadherin intercellular junctions. Major morphogenetic defects caused by abrogation of Nck signaling included loss of endothelial apical-basal polarity and impaired lumenization. Time-lapse imaging using a Förster resonance energy transfer biosensor, immunostaining with phospho-specific antibodies, and GST pull-down assays showed that Nck determines spatiotemporal patterns of Cdc42/aPKC activation during endothelial morphogenesis. Our results demonstrate that Nck acts as an important hub integrating angiogenic cues with cytoskeletal changes that enable endothelial apical-basal polarization and lumen formation. These findings point to Nck as an emergent target for effective antiangiogenic therapy.

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Rodríguez-Fraticelli, Alejo E., Muriel Auzan, Miguel A. Alonso, Michel Bornens, and Fernando Martín-Belmonte. "Cell confinement controls centrosome positioning and lumen initiation during epithelial morphogenesis." Journal of Cell Biology 198, no. 6 (September 10, 2012): 1011–23. http://dx.doi.org/10.1083/jcb.201203075.

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Epithelial organ morphogenesis involves sequential acquisition of apicobasal polarity by epithelial cells and development of a functional lumen. In vivo, cells perceive signals from components of the extracellular matrix (ECM), such as laminin and collagens, as well as sense physical conditions, such as matrix stiffness and cell confinement. Alteration of the mechanical properties of the ECM has been shown to promote cell migration and invasion in cancer cells, but the effects on epithelial morphogenesis have not been characterized. We analyzed the effects of cell confinement on lumen morphogenesis using a novel, micropatterned, three-dimensional (3D) Madin-Darby canine kidney cell culture method. We show that cell confinement, by controlling cell spreading, limits peripheral actin contractility and promotes centrosome positioning and lumen initiation after the first cell division. In addition, peripheral actin contractility is mediated by master kinase Par-4/LKB1 via the RhoA–Rho kinase–myosin II pathway, and inhibition of this pathway restores lumen initiation in minimally confined cells. We conclude that cell confinement controls nuclear–centrosomal orientation and lumen initiation during 3D epithelial morphogenesis.

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Hirai, Yohei, Derek Radisky, Rosanne Boudreau, Marina Simian, Mary E. Stevens, Yumiko Oka, Kyoko Takebe, Shinichiro Niwa, and Mina J. Bissell. "Epimorphin Mediates Mammary Luminal Morphogenesis through Control of C/EBPβ." Journal of Cell Biology 153, no. 4 (May 14, 2001): 785–94. http://dx.doi.org/10.1083/jcb.153.4.785.

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We have shown previously that epimorphin (EPM), a protein expressed on the surface of myoepithelial and fibroblast cells of the mammary gland, acts as a multifunctional morphogen of mammary epithelial cells. Here, we present the molecular mechanism by which EPM mediates luminal morphogenesis. Treatment of cells with EPM to induce lumen formation greatly increases the overall expression of transcription factor CCAAT/enhancer binding protein (C/EBP)β and alters the relative expression of its two principal isoforms, LIP and LAP. These alterations were shown to be essential for the morphogenetic activities, since constitutive expression of LIP was sufficient to produce lumen formation, whereas constitutive expression of LAP blocked EPM-mediated luminal morphogenesis. Furthermore, in a transgenic mouse model in which EPM expression was expressed in an apolar fashion on the surface of mammary epithelial cells, we found increased expression of C/EBPβ, increased relative expression of LIP to LAP, and enlarged ductal lumina. Together, our studies demonstrate a role for EPM in luminal morphogenesis through control of C/EBPβ expression.

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Jung, Jae-Joon, Shivangi M. Inamdar, Ajit Tiwari, Ding Ye, Fang Lin, and Amit Choudhury. "Syntaxin 16 Regulates Lumen Formation during Epithelial Morphogenesis." PLoS ONE 8, no. 4 (April 23, 2013): e61857. http://dx.doi.org/10.1371/journal.pone.0061857.

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Montesano, R. "Retinoids induce lumen morphogenesis in mammary epithelial cells." Journal of Cell Science 115, no. 23 (December 1, 2002): 4419–31. http://dx.doi.org/10.1242/jcs.00164.

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Rodriguez-Fraticelli, Alejo E., Silvia Vergarajauregui, Dennis J. Eastburn, Anirban Datta, Miguel A. Alonso, Keith Mostov, and Fernando Martín-Belmonte. "The Cdc42 GEF Intersectin 2 controls mitotic spindle orientation to form the lumen during epithelial morphogenesis." Journal of Cell Biology 189, no. 4 (May 17, 2010): 725–38. http://dx.doi.org/10.1083/jcb.201002047.

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Epithelial organs are made of tubes and cavities lined by a monolayer of polarized cells that enclose the central lumen. Lumen formation is a crucial step in the formation of epithelial organs. The Rho guanosine triphosphatase (GTPase) Cdc42, which is a master regulator of cell polarity, regulates the formation of the central lumen in epithelial morphogenesis. However, how Cdc42 is regulated during this process is still poorly understood. Guanine nucleotide exchange factors (GEFs) control the activation of small GTPases. Using the three-dimensional Madin–Darby canine kidney model, we have identified a Cdc42-specific GEF, Intersectin 2 (ITSN2), which localizes to the centrosomes and regulates Cdc42 activation during epithelial morphogenesis. Silencing of either Cdc42 or ITSN2 disrupts the correct orientation of the mitotic spindle and normal lumen formation, suggesting a direct relationship between these processes. Furthermore, we demonstrated this direct relationship using LGN, a component of the machinery for mitotic spindle positioning, whose disruption also results in lumen formation defects.

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Willenborg, Carly, Jian Jing, Christine Wu, Hugo Matern, Jerome Schaack, Jemima Burden, and Rytis Prekeris. "Interaction between FIP5 and SNX18 regulates epithelial lumen formation." Journal of Cell Biology 195, no. 1 (October 3, 2011): 71–86. http://dx.doi.org/10.1083/jcb.201011112.

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During the morphogenesis of the epithelial lumen, apical proteins are thought to be transported via endocytic compartments to the site of the forming lumen, although the machinery mediating this transport remains to be elucidated. Rab11 GTPase and its binding protein, FIP5, are important regulators of polarized endocytic transport. In this study, we identify sorting nexin 18 as a novel FIP5-interacting protein and characterize the role of FIP5 and SNX18 in epithelial lumen morphogenesis. We show that FIP5 mediates the transport of apical proteins from apical endosomes to the apical plasma membrane and, along with SNX18, is required for the early stages of apical lumen formation. Furthermore, both proteins bind lipids, and FIP5 promotes the capacity of SNX18 to tubulate membranes, which implies a role for FIP5 and SNX18 in endocytic carrier formation and/or scission. In summary, the present findings support the hypothesis that this FIP5-SNX18 complex plays a pivotal role in the polarized transport of apical proteins during apical lumen initiation in epithelial cells.

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Navis, Adam, and Celeste M. Nelson. "Pulling together: Tissue-generated forces that drive lumen morphogenesis." Seminars in Cell & Developmental Biology 55 (July 2016): 139–47. http://dx.doi.org/10.1016/j.semcdb.2016.01.002.

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Bayless, Kayla J., and George E. Davis. "The Cdc42 and Rac1 GTPases are required for capillary lumen formation in three-dimensional extracellular matrices." Journal of Cell Science 115, no. 6 (March 15, 2002): 1123–36. http://dx.doi.org/10.1242/jcs.115.6.1123.

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Here we show a requirement for the Cdc42 and Rac1 GTPases in endothelial cell (EC) morphogenesis in three-dimensional extracellular matrices. Cdc42 and Rac1 specifically regulate EC intracellular vacuole and lumen formation in both collagen and fibrin matrices. Clostridium difficile toxin B(which blocks all three Rho GTPases) completely inhibited the ability of ECs to form both vacuoles and lumens, whereas C3 transferase, a selective inhibitor of Rho, did not. Expression of either dominant-negative (N17) or constitutively active (V12) Cdc42 using recombinant adenoviruses dramatically inhibited EC vacuole and lumen formation in both collagen and fibrin matrices. Both vacuole and lumen formation initiated in ECs expressing dominant-negative(N17) Rac1 but later collapsed, indicating a role for Rac1 during later stages of vessel development. Analysis of cultures using confocal microscopy revealed green fluorescent protein-V12Rac1, -Rac1 wild-type and -Cdc42 wild-type chimeric proteins targeted to intracellular vacuole membranes during the lumen formation process. Also, expression of the verprolin-cofilin-acidic domain of N-WASP, a downstream Cdc42 effector, in ECs completely interfered with vacuole and lumen formation. These results collectively reveal a novel role for Cdc42 and Rac1 in the process of EC vacuole and lumen formation in three-dimensional extracellular matrices.

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Tanimizu, Naoki, Atsushi Miyajima, and Keith E. Mostov. "Liver Progenitor Cells Fold Up a Cell Monolayer into a Double-layered Structure during Tubular Morphogenesis." Molecular Biology of the Cell 20, no. 9 (May 2009): 2486–94. http://dx.doi.org/10.1091/mbc.e08-02-0177.

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Bile ducts are hepatic tubular structures that are lined by cholangiocytes, a type of liver epithelial cell. Cholangiocytes first form a single layer of cells, termed the ductal plate, surrounding the portal vein, which eventually remodels into the branching tubular network of bile ducts. The process of bile duct morphogenesis is not yet clear: a conventional model where cholangiocytes proliferate to duplicate a single layer of the ductal plate before lumen formation seems inconsistent with the observation that proliferation is dramatically reduced when hepatoblasts, liver progenitor cells, differentiate into cholangiocytes. Here, we developed a new culture system in which a liver progenitor cell line, HPPL, reorganizes from a monolayer to tubular structures in response to being overlaid with a gel containing type I collagen and Matrigel. We found that some of the HPPL in the monolayer depolarized and migrated to fold up the monolayer into a double-cell layer. These morphogenetic processes occurred without cell proliferation and required phosphatidylinositol 3-kinase and Akt activity. Later in morphogenesis, luminal space was generated between the two cell layers. This process, in particular enlargement of the apical lumen, involved transcriptional activity of HNF1β. Thus, using this sandwich culture system, we could segregate tubulogenesis of bile ducts into distinct steps and found that the PI3K/Akt pathway and HNF1β regulated different steps of the morphogenesis. Although the process of tubulogenesis in culture specifically resembled early bile duct formation, involvement of these two key players suggests that the sandwich culture might help us to find common principles of tubulogenesis in general.

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Vogler, Georg, Jiandong Liu, Timothy W. Iafe, Ede Migh, József Mihály, and Rolf Bodmer. "Cdc42 and formin activity control non-muscle myosin dynamics during Drosophila heart morphogenesis." Journal of Cell Biology 206, no. 7 (September 29, 2014): 909–22. http://dx.doi.org/10.1083/jcb.201405075.

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During heart formation, a network of transcription factors and signaling pathways guide cardiac cell fate and differentiation, but the genetic mechanisms orchestrating heart assembly and lumen formation remain unclear. Here, we show that the small GTPase Cdc42 is essential for Drosophila melanogaster heart morphogenesis and lumen formation. Cdc42 genetically interacts with the cardiogenic transcription factor tinman; with dDAAM which belongs to the family of actin organizing formins; and with zipper, which encodes nonmuscle myosin II. Zipper is required for heart lumen formation, and its spatiotemporal activity at the prospective luminal surface is controlled by Cdc42. Heart-specific expression of activated Cdc42, or the regulatory formins dDAAM and Diaphanous caused mislocalization of Zipper and induced ectopic heart lumina, as characterized by luminal markers such as the extracellular matrix protein Slit. Placement of Slit at the lumen surface depends on Cdc42 and formin function. Thus, Cdc42 and formins play pivotal roles in heart lumen formation through the spatiotemporal regulation of the actomyosin network.

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Connolly, John O., Nandi Simpson, Lindsay Hewlett, and Alan Hall. "Rac Regulates Endothelial Morphogenesis and Capillary Assembly." Molecular Biology of the Cell 13, no. 7 (July 2002): 2474–85. http://dx.doi.org/10.1091/mbc.e02-01-0006.

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Endothelial cells undergo branching morphogenesis to form capillary tubes. We have utilized an in vitro Matrigel overlay assay to analyze the role of the cytoskeleton and Rho GTPases during this process. The addition of matrix first induces changes in cell morphology characterized by the formation of dynamic cellular protrusions and the assembly of discrete aggregates or cords of aligned cells resembling primitive capillary-like structures, but without a recognizable lumen. This is followed by cell migration leading to the formation of a complex interconnecting network of capillary tubes with readily identifiable lumens. Inhibition of actin polymerization or actin-myosin contraction inhibits cell migration but has no effect on the initial changes in endothelial cell morphology. However, inhibition of microtubule dynamics prevents both the initial cell shape changes as well as cell migration. We find that the small GTPase Rac is essential for the matrix-induced changes in endothelial cell morphology, whereas p21-activated kinase, an effector of Rac, is required for cell motility. We conclude that Rac integrates signaling through both the actin and microtubule cytoskeletons to promote capillary tube assembly.

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Helenius, Iiro Taneli, and Greg J. Beitel. "The first “Slit” is the deepest: the secret to a hollow heart." Journal of Cell Biology 182, no. 2 (July 28, 2008): 221–23. http://dx.doi.org/10.1083/jcb.200806186.

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Tubular organs are essential for life, but lumen formation in nonepithelial tissues such as the vascular system or heart is poorly understood. Two studies in this issue (Medioni, C., M. Astier, M. Zmojdzian, K. Jagla, and M. Sémériva. 2008. J. Cell Biol. 182:249–261; Santiago-Martínez, E., N.H. Soplop, R. Patel, and S.G. Kramer. 2008. J. Cell Biol. 182:241–248) reveal unexpected roles for the Slit–Robo signaling system during Drosophila melanogaster heart morphogenesis. In cardioblasts, Slit and Robo modulate the cell shape changes and domains of E-cadherin–based adhesion that drive lumen formation. Furthermore, in contrast to the well-known paracrine role of Slit and Robo in guiding cell migrations, here Slit and Robo may act by autocrine signaling. In addition, the two groups demonstrate that heart lumen formation is even more distinct from typical epithelial tubulogenesis mechanisms because the heart lumen is bounded by membrane surfaces that have basal rather than apical attributes. As the D. melanogaster cardioblasts are thought to have significant evolutionary similarity to vertebrate endothelial and cardiac lineages, these findings are likely to provide insights into mechanisms of vertebrate heart and vascular morphogenesis.

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Blasky, Alex J., Anthony Mangan, and Rytis Prekeris. "Polarized Protein Transport and Lumen Formation During Epithelial Tissue Morphogenesis." Annual Review of Cell and Developmental Biology 31, no. 1 (November 13, 2015): 575–91. http://dx.doi.org/10.1146/annurev-cellbio-100814-125323.

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Teshima, T. H. N., K. L. Wells, S. V. Lourenço, and A. S. Tucker. "Apoptosis in Early Salivary Gland Duct Morphogenesis and Lumen Formation." Journal of Dental Research 95, no. 3 (December 2015): 277–83. http://dx.doi.org/10.1177/0022034515619581.

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Willenborg, Carly, and Rytis Prekeris. "Apical protein transport and lumen morphogenesis in polarized epithelial cells." Bioscience Reports 31, no. 4 (March 2, 2011): 245–56. http://dx.doi.org/10.1042/bsr20100119.

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Segregation of the apical and basolateral plasma membrane domains is the key distinguishing feature of epithelial cells. A series of interrelated cues and processes follow this primary polarization event, resulting in the morphogenesis of the mammalian epithelium. This review focuses on the role of the interactions between the extracellular matrix and neighbouring cells during the initiation and establishment of epithelial polarity, and the role that membrane transport and polarity complexes play in this process. An overview of the formation of the apical junctional complexes is given in relation to the generation of distinct membrane domains characterized by the asymmetric distribution of phosphoinositides and proteins. The mechanisms and machinery utilized by the trafficking pathways involved in the generation and maintenance of this apical-basolateral polarization are expounded, highlighting processes of apical-directed transport. Furthermore, the current proposed mechanisms for the organization of entire networks of cells into a structured, polarized three-dimensional structure are described, with an emphasis on the proposed mechanisms for the formation and expansion of the apical lumen.

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Azizoglu, D. Berfin, Caitlin Braitsch, Denise K. Marciano, and Ondine Cleaver. "Afadin and RhoA control pancreatic endocrine mass via lumen morphogenesis." Genes & Development 31, no. 23-24 (December 1, 2017): 2376–90. http://dx.doi.org/10.1101/gad.307637.117.

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Wen, H. C., A. Avivar-Valderas, M. S. Sosa, N. Girnius, E. F. Farias, R. J. Davis, and J. A. Aguirre-Ghiso. "p38 Signaling Induces Anoikis and Lumen Formation During Mammary Morphogenesis." Science Signaling 4, no. 174 (May 24, 2011): ra34. http://dx.doi.org/10.1126/scisignal.2001684.

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Medioni, Caroline, Martine Astier, Monika Zmojdzian, Krzysztof Jagla, and Michel Sémériva. "Genetic control of cell morphogenesis during Drosophila melanogaster cardiac tube formation." Journal of Cell Biology 182, no. 2 (July 28, 2008): 249–61. http://dx.doi.org/10.1083/jcb.200801100.

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Tubulogenesis is an essential component of organ development, yet the underlying cellular mechanisms are poorly understood. We analyze here the formation of the Drosophila melanogaster cardiac lumen that arises from the migration and subsequent coalescence of bilateral rows of cardioblasts. Our study of cell behavior using three-dimensional and time-lapse imaging and the distribution of cell polarity markers reveals a new mechanism of tubulogenesis in which repulsion of prepatterned luminal domains with basal membrane properties and cell shape remodeling constitute the main driving forces. Furthermore, we identify a genetic pathway in which roundabout, slit, held out wings, and dystroglycan control cardiac lumen formation by establishing nonadherent luminal membranes and regulating cell shape changes. From these data we propose a model for D. melanogaster cardiac lumen formation, which differs, both at a cellular and molecular level, from current models of epithelial tubulogenesis. We suggest that this new example of tube formation may be helpful in studying vertebrate heart tube formation and primary vasculogenesis.

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López, Tomas, Minerva Camacho, Margarita Zayas, Rebeca Nájera, Rosana Sánchez, Carlos F. Arias, and Susana López. "Silencing the Morphogenesis of Rotavirus." Journal of Virology 79, no. 1 (January 1, 2005): 184–92. http://dx.doi.org/10.1128/jvi.79.1.184-192.2005.

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ABSTRACT The morphogenesis of rotaviruses follows a unique pathway in which immature double-layered particles (DLPs) assembled in the cytoplasm bud across the membrane of the endoplasmic reticulum (ER), acquiring during this process a transient lipid membrane which is modified with the ER resident viral glycoproteins NSP4 and VP7; these enveloped particles also contain VP4. As the particles move towards the interior of the ER cisternae, the transient lipid membrane and the nonstructural protein NSP4 are lost, while the virus surface proteins VP4 and VP7 rearrange to form the outermost virus protein layer, yielding mature infectious triple-layered particles (TLPs). In this work, we have characterized the role of NSP4 and VP7 in rotavirus morphogenesis by silencing the expression of both glycoproteins through RNA interference. Silencing the expression of either NSP4 or VP7 reduced the yield of viral progeny by 75 to 80%, although the underlying mechanism of this reduction was different in each case. Blocking the synthesis of NSP4 affected the intracellular accumulation and the cellular distribution of several viral proteins, and little or no virus particles (neither DLPs nor TLPs) were assembled. VP7 silencing, in contrast, did not affect the expression or distribution of other viral proteins, but in its absence, enveloped particles accumulated within the lumen of the ER, and no mature infectious virus was produced. Altogether, these results indicate that during a viral infection, NSP4 serves as a receptor for DLPs on the ER membrane and drives the budding of these particles into the ER lumen, while VP7 is required for removing the lipid envelope during the final step of virus morphogenesis.

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Reginato, Mauricio J., Kenna R. Mills, Esther B. E. Becker, Danielle K. Lynch, Azad Bonni, Senthil K. Muthuswamy, and Joan S. Brugge. "Bim Regulation of Lumen Formation in Cultured Mammary Epithelial Acini Is Targeted by Oncogenes." Molecular and Cellular Biology 25, no. 11 (June 1, 2005): 4591–601. http://dx.doi.org/10.1128/mcb.25.11.4591-4601.2005.

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ABSTRACT Epithelial cells organize into cyst-like structures that contain a spherical monolayer of cells that enclose a central lumen. Using a three-dimensional basement membrane culture model in which mammary epithelial cells form hollow, acinus-like structures, we previously demonstrated that lumen formation is achieved, in part, through apoptosis of centrally localized cells. We demonstrate that the proapoptotic protein Bim may selectively trigger apoptosis of the centrally localized acinar cells, leading to temporally controlled lumen formation. Bim is not detectable during early stages of three-dimensional mammary acinar morphogenesis and is then highly upregulated in all cells of acini, coincident with detection of apoptosis in the centrally localized acinar cells. Inhibition of Bim expression by RNA interference transiently blocks luminal apoptosis and delays lumen formation. Oncogenes that induce acinar luminal filling, such as ErbB2 and v-Src, suppress expression of Bim through a pathway dependent on Erk-mitogen-activated protein kinase; however, HPV 16 E7, an oncogene that stimulates cell proliferation but not luminal filling, is unable to reduce Bim expression. Thus, Bim is a critical regulator of luminal apoptosis during mammary acinar morphogenesis in vitro and may be an important target of oncogenes that disrupt glandular epithelial architecture.

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Whelan, Kelly A., Sarah A. Caldwell, Kristina S. Shahriari, S. RaElle Jackson, Lisa D. Franchetti, Gregg J. Johannes, and Mauricio J. Reginato. "Hypoxia Suppression of Bim and Bmf Blocks Anoikis and Luminal Clearing during Mammary Morphogenesis." Molecular Biology of the Cell 21, no. 22 (November 15, 2010): 3829–37. http://dx.doi.org/10.1091/mbc.e10-04-0353.

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Proper adhesion to extracellular matrix is critical for epithelial cell survival. Detachment from matrix signals results in apoptosis, referred to as anoikis. Selective apoptosis of cells that become detached from matrix is associated with the formation of a lumen in three-dimensional mammary epithelial acinar structures in vitro. Because early breast cancer lesions such as carcinoma in situ, characterized by ducts exhibiting lumens filled with cells, are often associated with hypoxic markers, we sought to examine the role of hypoxia in anoikis and lumen formation in mammary epithelial cells. Here, we show that hypoxic conditions inhibit anoikis and block expression of proapoptotic BH3-only family members Bim and Bmf in epithelial cells. Hypoxia-mediated anoikis protection is associated with increased activation of the epidermal growth factor receptor–mitogen-activated protein kinase kinase–extracellular signal-regulated kinase (Erk) kinase pathway and requires the hypoxia-activated transcription factor. Consistent with these data, hypoxic conditions inhibit luminal clearing during morphogenesis in human mammary epithelial acini when grown in three-dimensional cultures and are associated with decreased expression of Bim and Bmf as well as Erk activation. We show that hypoxia regulates specific cell survival pathways that disrupt tissue architecture related to clearing of luminal space during mammary morphogenesis and suggest that hypoxia-mediated anoikis resistance may contribute to cancer progression.

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Yuan, Lei, Anastasia Sacharidou, Amber N. Stratman, Alexandra Le Bras, Peter J. Zwiers, Katherine Spokes, Manoj Bhasin, et al. "RhoJ is an endothelial cell-restricted Rho GTPase that mediates vascular morphogenesis and is regulated by the transcription factor ERG." Blood 118, no. 4 (July 28, 2011): 1145–53. http://dx.doi.org/10.1182/blood-2010-10-315275.

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Abstract ERG is a member of the ETS transcription factor family that is highly enriched in endothelial cells (ECs). To further define the role of ERG in regulating EC function, we evaluated the effect of ERG knock-down on EC lumen formation in 3D collagen matrices. Blockade of ERG using siRNA completely interferes with EC lumen formation. Quantitative PCR (QPCR) was used to identify potential downstream gene targets of ERG. In particular, we identified RhoJ as the Rho GTPase family member that is closely related to Cdc42 as a target of ERG. Knockdown of ERG expression in ECs led to a 75% reduction in the expression of RhoJ. Chromatin immunoprecipitation and transactivation studies demonstrated that ERG could bind to functional sites in the proximal promoter of the RhoJ gene. Knock-down of RhoJ similarly resulted in a marked reduction in the ability of ECs to form lumens. Suppression of either ERG or RhoJ during EC lumen formation was associated with a marked increase in RhoA activation and a decrease in Rac1 and Cdc42 activation and their downstream effectors. Finally, in contrast to other Rho GTPases, RhoJ exhibits a highly EC-restricted expression pattern in several different tissues, including the brain, heart, lung, and liver.

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Nawrot, Dorota A., Lutfiye Yildiz Ozer, and Ayman Al Haj Zen. "A Novel High Content Angiogenesis Assay Reveals That Lacidipine, L-Type Calcium Channel Blocker, Induces In Vitro Vascular Lumen Expansion." International Journal of Molecular Sciences 23, no. 9 (April 28, 2022): 4891. http://dx.doi.org/10.3390/ijms23094891.

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Angiogenesis is a critical cellular process toward establishing a functional circulatory system capable of delivering oxygen and nutrients to the tissue in demand. In vitro angiogenesis assays represent an important tool for elucidating the biology of blood vessel formation and for drug discovery applications. Herein, we developed a novel, high content 2D angiogenesis assay that captures endothelial morphogenesis’s cellular processes, including lumen formation. In this assay, endothelial cells form luminized vascular-like structures in 48 h. The assay was validated for its specificity and performance. Using the optimized assay, we conducted a phenotypic screen of a library containing 150 FDA-approved cardiovascular drugs to identify modulators of lumen formation. The screening resulted in several L-type calcium channel blockers being able to expand the lumen space compared to controls. Among these blockers, Lacidipine was selected for follow-up studies. We found that the endothelial cells treated with Lacidipine showed enhanced activity of caspase-3 in the luminal space. Pharmacological inhibition of caspase activity abolished the Lacidipine-enhancing effect on lumen formation, suggesting the involvement of apoptosis. Using a Ca2+ biosensor, we found that Lacipidine reduces the intracellular Ca2+ oscillations amplitude in the endothelial cells at the early stage, whereas Lacidipine blocks these Ca2+ oscillations completely at the late stage. The inhibition of MLCK exhibits a phenotype of lumen expansion similar to that of Lacidipine. In conclusion, this study describes a novel high-throughput phenotypic assay to study angiogenesis. Our findings suggest that calcium signalling plays an essential role during lumen morphogenesis. L-type Ca2+ channel blockers could be used for more efficient angiogenesis-mediated therapies.

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Nogawa, H., and T. Ito. "Branching morphogenesis of embryonic mouse lung epithelium in mesenchyme-free culture." Development 121, no. 4 (April 1, 1995): 1015–22. http://dx.doi.org/10.1242/dev.121.4.1015.

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Embryonic mouse lung epithelium was separated from its mesenchyme and cultured under mesenchyme-free conditions. When covered with Matrigel, the cultured epithelium underwent branching morphogenesis in medium containing acidic fibroblast growth factor (aFGF), in which the epithelial cells constructed a simple columnar cell layer forming a lumen, as seen in normal development. The epithelial growth and branching morphogenesis induced by aFGF was completely inhibited by an antibody against aFGF. Heparin caused extra epithelial growth in cooperation with aFGF, but its use resulted in luminal expansion instead of enhanced branching. Basic FGF induced abnormal morphogenesis of the epithelium, though the lumen formed was lined by a simple columnar cell layer. Epidermal growth factor could not maintain epithelial cell growth, and the epithelium became a smaller and smoother ball than that at the start of cultivation. When covered with a collagen gel instead of Matrigel, the epithelium remained in its initial form, neither newly branching nor becoming a smooth ball, in the presence of aFGF. These results show that the epithelium of lung rudiments was able to branch under mesenchyme-free culture conditions in which a basement membrane matrix and aFGF were substitutes for the mesenchyme.

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Yates, Laura, Carsten Schnatwinkel, Lee Hazelwood, Lauren Chessum, Anju Paudyal, Clare Lloyd, Lee Niswander, Andy Greenfield, and Charlotte Dean. "Scribble is required for normal lumen morphogenesis in the mammalian lung." Developmental Biology 356, no. 1 (August 2011): 122. http://dx.doi.org/10.1016/j.ydbio.2011.05.072.

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Hsouna, Anita, Gouthami Nallamothu, Nurgun Kose, Maria Guinea, Vincent Dammai, and Tien Hsu. "Drosophila von Hippel-Lindau Tumor Suppressor Gene Function in Epithelial Tubule Morphogenesis." Molecular and Cellular Biology 30, no. 15 (June 1, 2010): 3779–94. http://dx.doi.org/10.1128/mcb.01578-09.

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ABSTRACT Mutations in the human von Hippel-Lindau (VHL) gene are the cause of VHL disease that displays multiple benign and malignant tumors. The VHL gene has been shown to regulate angiogenic potential and glycolic metabolism via its E3 ubiquitin ligase function against the alpha subunit of hypoxia-inducible factor (HIF-α). However, many HIF-independent functions of VHL have been identified. Recent evidence also indicates that the canonical function cannot fully explain the VHL mutant cell phenotypes, although it is still unclear how many of these noncanonical functions relate to the pathophysiological processes because of a lack of tractable genetic systems. Here, we report the first genomic mutant phenotype of Drosophila melanogaster VHL (dVHL) in the epithelial tubule network, the trachea, and show that dVHL regulates branch migration and lumen formation via its endocytic function. The endocytic function regulates the surface level of the chemotactic signaling receptor Breathless and promotes clearing of the lumen matrix during maturation of the tracheal tubes. Importantly, the regulatory function in tubular morphogenesis is conserved in the mammalian system, as conditional knockout of Vhl in mouse kidney also resulted in similar cell motility and lumen phenotypes.

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Wang, Sicong, Chien-Wei Lin, Amber E. Carleton, Chari L. Cortez, Craig Johnson, Linnea E. Taniguchi, Nikola Sekulovski, et al. "Spatially resolved cell polarity proteomics of a human epiblast model." Science Advances 7, no. 17 (April 2021): eabd8407. http://dx.doi.org/10.1126/sciadv.abd8407.

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Critical early steps in human embryonic development include polarization of the inner cell mass, followed by formation of an expanded lumen that will become the epiblast cavity. Recently described three-dimensional (3D) human pluripotent stem cell–derived cyst (hPSC-cyst) structures can replicate these processes. To gain mechanistic insights into the poorly understood machinery involved in epiblast cavity formation, we interrogated the proteomes of apical and basolateral membrane territories in 3D human hPSC-cysts. APEX2-based proximity bioinylation, followed by quantitative mass spectrometry, revealed a variety of proteins without previous annotation to specific membrane subdomains. Functional experiments validated the requirement for several apically enriched proteins in cyst morphogenesis. In particular, we found a key role for the AP-1 clathrin adaptor complex in expanding the apical membrane domains during lumen establishment. These findings highlight the robust power of this proximity labeling approach for discovering novel regulators of epithelial morphogenesis in 3D stem cell–based models.

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Wang, A. Z., G. K. Ojakian, and W. J. Nelson. "Steps in the morphogenesis of a polarized epithelium. I. Uncoupling the roles of cell-cell and cell-substratum contact in establishing plasma membrane polarity in multicellular epithelial (MDCK) cysts." Journal of Cell Science 95, no. 1 (January 1, 1990): 137–51. http://dx.doi.org/10.1242/jcs.95.1.137.

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The development of cell polarity in Madin-Darby canine kidney (MDCK) cells has been analyzed under conditions in which cells are induced to form multicellular epithelial cysts in stages that mimic the ontogeny of epithelial tissues and organs in vivo. The morphogenesis of MDCK cysts in suspension culture or in a collagen gel proceeds in distinct stages involving the initial aggregation of cells followed by development of a closed monolayer of polarized epithelial cells that surrounds a central lumen. The polarity of cells was determined at each stage by analyzing the distributions of marker proteins of the apical (gp135) and basal-lateral (Na+,K(+)-ATPase) domains of the plasma membrane, the tight junction (ZO-1) and proteins involved in cell-cell (uvomorulin) and cell-substratum contact (type IV collagen). We show that cells have a distinctive and opposite polarity in cysts formed in suspension culture compared to those formed in collagen gels. In suspension culture, the basal-lateral membrane faces the central lumen and the apical membrane faces the outside, whereas in collagen gel, the basal-lateral membrane faces the outside collagen and the apical membrane faces the central lumen. Detailed analysis of the distributions of marker proteins during the morphogenesis of these three-dimensional structures indicates that: (1) cell-cell contact is sufficient to trigger the segregation of marker proteins of the apical and basal-lateral membrane domains to distinct regions of the membrane; (2) cell-cell contact induces association of the tight junction protein ZO-1 with the contact zone between cells; (3) localization of the tight junction protein ZO-1 to the apex of the lateral membrane and the establishment of the epithelial axis, however, requires the formation of a basal lamina and cell-substratum contact; (4) in suspension culture, MDCK cysts secrete and establish a basal lamina in the central lumen. These results show that cell-cell and cell-substratum contact have distinct roles in the morphogenesis of polarized epithelia. We suggest that the mechanisms involved in triggering cell polarity may be common to different polarized epithelia in vivo.

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Le Verge-Serandour, Mathieu, and Hervé Turlier. "A hydro-osmotic coarsening theory of biological cavity formation." PLOS Computational Biology 17, no. 9 (September 3, 2021): e1009333. http://dx.doi.org/10.1371/journal.pcbi.1009333.

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Fluid-filled biological cavities are ubiquitous, but their collective dynamics has remained largely unexplored from a physical perspective. Based on experimental observations in early embryos, we propose a model where a cavity forms through the coarsening of myriad of pressurized micrometric lumens, that interact by ion and fluid exchanges through the intercellular space. Performing extensive numerical simulations, we find that hydraulic fluxes lead to a self-similar coarsening of lumens in time, characterized by a robust dynamic scaling exponent. The collective dynamics is primarily controlled by hydraulic fluxes, which stem from lumen pressures differences and are dampened by water permeation through the membrane. Passive osmotic heterogeneities play, on the contrary, a minor role on cavity formation but active ion pumping can largely modify the coarsening dynamics: it prevents the lumen network from a collective collapse and gives rise to a novel coalescence-dominated regime exhibiting a distinct scaling law. Interestingly, we prove numerically that spatially biasing ion pumping may be sufficient to position the cavity, suggesting a novel mode of symmetry breaking to control tissue patterning. Providing generic testable predictions, our model forms a comprehensive theoretical basis for hydro-osmotic interaction between biological cavities, that shall find wide applications in embryo and tissue morphogenesis.

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XIAO, Chun, Huo-Zhen HU, and Xian-Ming MO. "Lumen morphogenesis and molecular mechanisms in tubular organs during zebrafish embryonic development." Hereditas (Beijing) 35, no. 4 (September 28, 2013): 449–58. http://dx.doi.org/10.3724/sp.j.1005.2013.00449.

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Reginato, Mauricio J., and Senthil K. Muthuswamy. "Illuminating the Center: Mechanisms Regulating Lumen Formation and Maintenance in Mammary Morphogenesis." Journal of Mammary Gland Biology and Neoplasia 11, no. 3-4 (November 18, 2006): 205–11. http://dx.doi.org/10.1007/s10911-006-9030-4.

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Farooqui, Sarfarazhussain, Mark W. Pellegrino, Ivo Rimann, Matthias K. Morf, Louisa Müller, Erika Fröhli, and Alex Hajnal. "Coordinated Lumen Contraction and Expansion during Vulval Tube Morphogenesis in Caenorhabditis elegans." Developmental Cell 23, no. 3 (September 2012): 494–506. http://dx.doi.org/10.1016/j.devcel.2012.06.019.

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Lu, Ruifeng, Debra L. Johnson, Lorraine Stewart, Kelsey Waite, David Elliott, and Jean M. Wilson. "Rab14 regulation of claudin-2 trafficking modulates epithelial permeability and lumen morphogenesis." Molecular Biology of the Cell 25, no. 11 (June 2014): 1744–54. http://dx.doi.org/10.1091/mbc.e13-12-0724.

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Regulation of epithelial barrier function requires targeted insertion of tight junction proteins that have distinct selectively permeable characteristics. The insertion of newly synthesized proteins and recycling of internalized tight junction components control both polarity and junction function. Here we show that the small GTPase Rab14 regulates tight junction structure. In Madin–Darby canine kidney (MDCK) II cells, Rab14 colocalizes with junctional proteins, and knockdown of Rab14 results in increased transepithelial resistance. In cells without Rab14, there are small changes in the trafficking of claudin-1 and occludin. In addition, there is substantial depletion of the leaky claudin, claudin-2, but not other tight junction components. The loss of claudin-2 is complemented by inhibition of lysosomal function, suggesting that Rab14 sorts claudin-2 out of the lysosome-directed pathway. MDCK I cells lack claudin-2 endogenously, and knockdown of Rab14 in these cells does not result in a change in transepithelial resistance, suggesting that the effect is specific to claudin-2 trafficking. Furthermore, leaky claudins have been shown to be required for epithelial morphogenesis, and knockdown of Rab14 results in failure to form normal single-lumen cysts in three-dimensional culture. These results implicate Rab14 in specialized trafficking of claudin-2 from the recycling endosome.

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Göbel, Verena, Peter L. Barrett, David H. Hall, and John T. Fleming. "Lumen Morphogenesis in C. elegans Requires the Membrane-Cytoskeleton Linker erm-1." Developmental Cell 6, no. 6 (June 2004): 865–73. http://dx.doi.org/10.1016/j.devcel.2004.05.018.

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Martín-Belmonte, Fernando, Wei Yu, Alejo E. Rodríguez-Fraticelli, Andrew Ewald, Zena Werb, Miguel A. Alonso, and Keith Mostov. "Cell-Polarity Dynamics Controls the Mechanism of Lumen Formation in Epithelial Morphogenesis." Current Biology 18, no. 7 (April 2008): 507–13. http://dx.doi.org/10.1016/j.cub.2008.02.076.

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Martín-Belmonte, Fernando, Wei Yu, Alejo E. Rodríguez-Fraticelli, Andrew J. Ewald, Zena Werb, Miguel A. Alonso, and Keith Mostov. "Cell-Polarity Dynamics Controls the Mechanism of Lumen Formation in Epithelial Morphogenesis." Current Biology 18, no. 8 (April 2008): 630. http://dx.doi.org/10.1016/j.cub.2008.04.013.

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Martín-Belmonte, Fernando, Wei Yu, Alejo E. Rodríguez-Fraticelli, Andrew J. Ewald, Zena Werb, Miguel A. Alonso, and Keith Mostov. "Cell-Polarity Dynamics Controls the Mechanism of Lumen Formation in Epithelial Morphogenesis." Current Biology 18, no. 13 (July 2008): 1016. http://dx.doi.org/10.1016/j.cub.2008.06.055.

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Jia, Liwei, Fengming Liu, Steen H. Hansen, Martin B. A. ter Beest, and Mirjam M. P. Zegers. "Distinct roles of cadherin-6 and E-cadherin in tubulogenesis and lumen formation." Molecular Biology of the Cell 22, no. 12 (June 15, 2011): 2031–41. http://dx.doi.org/10.1091/mbc.e11-01-0038.

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Classic cadherins are important regulators of tissue morphogenesis. The predominant cadherin in epithelial cells, E-cadherin, has been extensively studied because of its critical role in normal epithelial development and carcinogenesis. Epithelial cells may also coexpress other cadherins, but their roles are less clear. The Madin Darby canine kidney (MDCK) cell line has been a popular mammalian model to investigate the role of E-cadherin in epithelial polarization and tubulogenesis. However, MDCK cells also express relatively high levels of cadherin-6, and it is unclear whether the functions of this cadherin are redundant to those of E-cadherin. We investigate the specific roles of both cadherins using a knockdown approach. Although we find that both cadherins are able to form adherens junctions at the basolateral surface, we show that they have specific and mutually exclusive roles in epithelial morphogenesis. Specifically, we find that cadherin-6 functions as an inhibitor of tubulogenesis, whereas E-cadherin is required for lumen formation. Ablation of cadherin-6 leads to the spontaneous formation of tubules, which depends on increased phosphoinositide 3-kinase (PI3K) activity. In contrast, loss of E-cadherin inhibits lumen formation by a mechanism independent of PI3K.

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Patient, Romuald, Christophe Hourioux, Pierre-Yves Sizaret, Sylvie Trassard, Camille Sureau, and Philippe Roingeard. "Hepatitis B Virus Subviral Envelope Particle Morphogenesis and Intracellular Trafficking." Journal of Virology 81, no. 8 (January 31, 2007): 3842–51. http://dx.doi.org/10.1128/jvi.02741-06.

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ABSTRACT Hepatitis B virus (HBV) is unusual in that its surface proteins (small [S], medium, and large [L]) are not only incorporated into the virion envelope but they also bud into empty subviral particles in great excess over virions. The morphogenesis of these subviral envelope particles remains unclear, but the S protein is essential and sufficient for budding. We show here that, in contrast to the presumed model, the HBV subviral particle formed by the S protein self-assembles into branched filaments in the lumen of the endoplasmic reticulum (ER). These long filaments are then folded and bridged for packing into crystal-like structures, which are then transported by ER-derived vesicles to the ER-Golgi intermediate compartment (ERGIC). Within the ERGIC, they are unpacked and relaxed, and their size and shape probably limits further progression through the secretory pathway. Such progression requires their conversion into spherical particles, which occurred spontaneously during the purification of these filaments by affinity chromatography. Small branched filaments are also formed by the L protein in the ER lumen, but these filaments are not packed into transport vesicles. They are transported less efficiently to the ERGIC, potentially accounting for the retention of the L protein within cells. These findings shed light on an important step in the HBV infectious cycle, as the intracellular accumulation of HBV subviral filaments may be directly linked to viral pathogenesis.

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Galaktionov, K. V., and I. I. Malkova. "Changes in the excretory bladder ultrastructure during the morphogenesis of Levinseniella brachysoma metacercariae." Journal of Helminthology 69, no. 3 (September 1995): 203–12. http://dx.doi.org/10.1017/s0022149x00014152.

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AbstractFor the first time the development of the excretory system Levinseniella brachysoma metacercariae (Trematoda: Microphallidae) obtained experimentally from Gammarus oceanicus has been described. The bladder wall of 8-day post-infection (P.I.) larvae consists of a syncytium covered with microvilli. Its cytoplasm contains well-developed rough endoplasmic reticulum (RER), free ribosomes, small oval dense mitochondria and numerous large membrane-bounded (about 5 μm in diameter) spherical granules. Later the size of the excretory bladder and the number of nuclei and RER cisternae increases. The large spherical granules disappear completely but spherical dense bodies (up to 4 μm in diameter) devoid of limiting membranes appear. The bladder lining forms thick columnar projections directed towards its lumen. Accumulations of microlamelli occur only on the lumen surface between adjacent projections. By the 42nd day P.I. the bladder wall has two separate components: the columnar projections and the syncytium between them.

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Khan, Liakot A., Gholamali Jafari, Nan Zhang, Edward Membreno, Siyang Yan, Hongjie Zhang, and Verena Gobel. "A tensile trilayered cytoskeletal endotube drives capillary-like lumenogenesis." Journal of Cell Biology 218, no. 7 (June 25, 2019): 2403–24. http://dx.doi.org/10.1083/jcb.201811175.

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Unicellular tubes are components of internal organs and capillaries. It is unclear how they meet the architectural challenge to extend a centered intracellular lumen of uniform diameter. In an RNAi-based Caenorhabditis elegans screen, we identified three intermediate filaments (IFs)—IFA-4, IFB-1, and IFC-2—as interactors of the lumenal membrane-actin linker ERM-1 in excretory-canal tubulogenesis. We find that IFs, generally thought to affect morphogenesis indirectly by maintaining tissue integrity, directly promote lumenogenesis in this capillary-like single-cell tube. We show that ERM-1, ACT-5/actin, and TBB-2/tubulin recruit membrane-forming endosomal and flux-promoting canalicular vesicles to the lumen, whereas IFs, themselves recruited to the lumen by ERM-1 and TBB-2, restrain lateral vesicle access. IFs thereby prevent cystogenesis, equilibrate the lumen diameter, and promote lumen forward extension. Genetic and imaging analyses suggest that IFB-1/IFA-4 and IFB-1/IFC-2 polymers form a perilumenal triple IF lattice, sandwiched between actin and helical tubulin. Our findings characterize a novel mechanism of capillary-like lumenogenesis, where a tensile trilayered cytoskeletal endotube transforms concentric into directional growth.

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Tanaka-Matakatsu, M., T. Uemura, H. Oda, M. Takeichi, and S. Hayashi. "Cadherin-mediated cell adhesion and cell motility in Drosophila trachea regulated by the transcription factor Escargot." Development 122, no. 12 (December 1, 1996): 3697–705. http://dx.doi.org/10.1242/dev.122.12.3697.

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Coordination of cell motility and adhesion is essential for concerted movement of tissues during animal morphogenesis. The Drosophila tracheal network is formed by branching, migration and fusion of tubular ectodermal epithelia. Tracheal tip cells, located at the end of each branch that is going to fuse, extend filopodia to search for targets and later change their cell shape to a seamless ring to allow passage of lumen. The cell adhesion molecule DE-cadherin accumulates at the site of contact to form a ring that marks the site of lumen entry and is essential for the fusion. DE-cadherin expression in tip cells of a subset of branches is dependent on escargot, a zinc finger gene expressed in all tip cells. Such escargot mutant tip cells failed to adhere to each other and continued to search for alternative targets by extending long filopodia. We present evidence indicating escargot positively regulates transcription of the DE-cadherin gene, shotgun. Overexpression of DE-cadherin rescued the defect in one of the fusion points in escargot mutants, demonstrating an essential role of DE-cadherin in target recognition and identifying escargot as a key regulator of cell adhesion and motility in tracheal morphogenesis.

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Romer, Anthony I., Jagmohan Singh, Satish Rattan, and Robert S. Krauss. "Smooth muscle fascicular reorientation is required for esophageal morphogenesis and dependent on Cdo." Journal of Cell Biology 201, no. 2 (April 8, 2013): 309–23. http://dx.doi.org/10.1083/jcb.201301005.

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Postnatal maturation of esophageal musculature involves proximal-to-distal replacement of smooth muscle with skeletal muscle by elusive mechanisms. We report that this process is impaired in mice lacking the cell surface receptor Cdo and identify the underlying developmental mechanism. A myogenic transition zone containing proliferative skeletal muscle precursor cells migrated in a proximal–distal direction, leaving differentiated myofibers in its wake. Distal to the transition zone, smooth muscle fascicles underwent a morphogenetic process whereby they changed their orientation relative to each other and to the lumen. Consequently, a path was cleared for the transition zone, and smooth muscle ultimately occupied only the distal-most esophagus; there was no loss of smooth muscle. Cdo−/− mice were specifically defective in fascicular reorientation, resulting in an aberrantly proximal skeletal–smooth muscle boundary. Furthermore, Cdo−/− mice displayed megaesophagus and achalasia, and their lower esophageal sphincter was resistant to nitric oxide–induced relaxation, suggesting a developmental linkage between patterning and sphincter function. Collectively, these results illuminate mechanisms of esophageal morphogenesis and motility disorders.

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Berson, Joanne F., Dawn C. Harper, Danielle Tenza, Graça Raposo, and Michael S. Marks. "Pmel17 Initiates Premelanosome Morphogenesis within Multivesicular Bodies." Molecular Biology of the Cell 12, no. 11 (November 2001): 3451–64. http://dx.doi.org/10.1091/mbc.12.11.3451.

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Melanosomes are tissue-specific organelles within which melanin is synthesized and stored. The melanocyte-specific glycoprotein Pmel17 is enriched in the lumen of premelanosomes, where it associates with characteristic striations of unknown composition upon which melanin is deposited. However, Pmel17 is synthesized as an integral membrane protein. To clarify its physical linkage to premelanosomes, we analyzed the posttranslational processing of human Pmel17 in pigmented and transfected nonpigmented cells. We show that Pmel17 is cleaved in a post-Golgi compartment into two disulfide-linked subunits: a large lumenal subunit, Mα, and an integral membrane subunit, Mβ. The two subunits remain associated intracellularly, indicating that detectable Mα remains membrane bound. We have previously shown that Pmel17 accumulates on intralumenal membrane vesicles and striations of premelanosomes in pigmented cells. In transfected nonpigmented cells Pmel17 associates with the intralumenal membrane vesicles of multivesicular bodies; cells overexpressing Pmel17 also display structures resembling premelanosomal striations within these compartments. These results suggest that Pmel17 is sufficient to drive the formation of striations from within multivesicular bodies and is thus directly involved in the biogenesis of premelanosomes.

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Goyal, Alka, Renu Singh, Elzbieta A. Swietlicki, Marc S. Levin, and Deborah C. Rubin. "Characterization of rat epimorphin/syntaxin 2 expression suggests a role in crypt-villus morphogenesis." American Journal of Physiology-Gastrointestinal and Liver Physiology 275, no. 1 (July 1, 1998): G114—G124. http://dx.doi.org/10.1152/ajpgi.1998.275.1.g114.

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The rodent intestinal mucosa undergoes a remarkable morphogenesis as the crypt-villus axis is formed. Endoderm-mesenchymal interactions play a critical role in this process. Epimorphin is a mesenchymal protein postulated to play a role in lung and skin morphogenesis. The rat homologue, syntaxin 2, belongs to a family of integral membrane proteins that function in vesicle docking and fusion. To clarify its role in fetal gut morphogenesis, epimorphin expression was examined during ontogeny, in an isograft model of ischemic injury and mucosal repair, and during intestinal adaptation after small bowel resection. Epimorphin/syntaxin 2 mRNA levels were increased in fetal gut during lumen formation and villus morphogenesis. mRNA levels remained elevated in the first 2 wk after birth and then declined at weaning. In situ hybridization showed epimorphin/syntaxin 2 mRNA in gestational day 14( G14) and G15 intestinal mesenchymal cells and in the mucosal lamina propria during villus formation. Epimorphin/syntaxin 2 mRNA expression increased during villus repair in the isograft. In contrast, in the early stages of intestinal adaptation after small bowel resection, epimorphin/syntaxin 2 mRNA expression was suppressed in the adapting gut. We conclude the cell-specific and temporal patterns of epimorphin expression in the models used in this study suggest a role in the morphogenesis of the crypt-villus axis.

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Stratman, Amber N., W. Brian Saunders, Anastasia Sacharidou, Wonshill Koh, Kevin E. Fisher, David C. Zawieja, Michael J. Davis, and George E. Davis. "Endothelial cell lumen and vascular guidance tunnel formation requires MT1-MMP–dependent proteolysis in 3-dimensional collagen matrices." Blood 114, no. 2 (July 9, 2009): 237–47. http://dx.doi.org/10.1182/blood-2008-12-196451.

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Abstract Here we show that endothelial cells (EC) require matrix type 1-metalloproteinase (MT1-MMP) for the formation of lumens and tube networks in 3-dimensional (3D) collagen matrices. A fundamental consequence of EC lumen formation is the generation of vascular guidance tunnels within collagen matrices through an MT1-MMP-dependent proteolytic process. Vascular guidance tunnels represent a conduit for EC motility within these spaces (a newly remodeled 2D matrix surface) to both assemble and remodel tube structures. Interestingly, it appears that twice as many tunnel spaces are created than are occupied by tube networks after several days of culture. After tunnel formation, these spaces represent a 2D migratory surface within 3D collagen matrices allowing for EC migration in an MMP-independent fashion. Blockade of EC lumenogenesis using inhibitors that interfere with the process (eg, integrin, MMP, PKC, Src) completely abrogates the formation of vascular guidance tunnels. Thus, the MT1-MMP-dependent proteolytic process that creates tunnel spaces is directly and functionally coupled to the signaling mechanisms required for EC lumen and tube network formation. In summary, a fundamental and previously unrecognized purpose of EC tube morphogenesis is to create networks of matrix conduits that are necessary for EC migration and tube remodeling events critical to blood vessel assembly.

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Journal articles on the topic 'Lumen Morphogenesis'

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