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WIREs Syst Biol Med
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Normal morphogenesis of epithelial tissues and progression of epithelial tumors

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Abstract Epithelial cells organize into various tissue architectures that largely maintain their structure throughout the life of an organism. For decades, the morphogenesis of epithelial tissues has fascinated scientists at the interface of cell, developmental, and molecular biology. Systems biology offers ways to combine knowledge from these disciplines by building integrative models that are quantitative and predictive. Can such models be useful for gaining a deeper understanding of epithelial morphogenesis? Here, we take inventory of some recurring themes in epithelial morphogenesis that systems approaches could strive to capture. Predictive understanding of morphogenesis at the systems level would prove especially valuable for diseases such as cancer, where epithelial tissue architecture is profoundly disrupted. WIREs Syst Biol Med 2012, 4:51–78. doi: 10.1002/wsbm.159 This article is categorized under: Physiology > Mammalian Physiology in Health and Disease

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Morphology of a polarized epithelial monolayer. (a) Vertical epithelial polarization into distinct apical, basal, and lateral plasma membrane domains. Apical surfaces contain specialized microvilli for absorption and secretion. Basal surfaces bind to extracellular matrix (ECM) proteins via integrins to assemble focal adhesions. Lateral membranes contain junctional complexes (tight junctions, adherens junctions, and desmosomes) that link the adjacent cells and provide diffusion barriers. (b) Horizontal epithelial polarization of core planar cell polarity (PCP) proteins. In the Drosophila wing, fz, dsh, and dgo localize to the distal cortical domains, whereas pk and Vang localize to the proximal cortical domains. Shortly after the maximal asymmetry of PCP proteins is observed, actin‐rich prehairs initiate from the distal domain of the cells. (c) Intracellular tension and intercellular forces shape epithelial morphology. Apical constriction results from the counterbalance of cortical tension and cellular adhesion. This constriction contributes line tensions at the interface between cells and serves as an energy barrier to cellular rearrangements.

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Building epithelial tissue architecture from tubes, branches, and acini. (a) Epithelial tubes are cylindrical monolayers with inner apical surfaces and outside basal surfaces that surround a central lumen. (b) Branched tubular networks result from epithelial extensions and bifurcations into the surrounding stroma. (c) Hollow spherical acini often terminate complex networks of branched tubes.

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Diffusible factors involved in epithelial morphogenesis. (a) Hepatocyte growth factor (HGF) signaling. Ligand binding to the HGF receptor (HGFR) leads to tyrosine autophosphorylation and Ras–MAPK (mitogen‐activated protein kinase) signaling. (b) Fibroblast growth factor (FGF) signaling. Ligand binding to the FGF receptor (FGFR) leads to tyrosine autophosphorylation and recruitment of fibroblast growth factor receptor substrate 2 (FRS2) to activate Ras–MAPK and phosphoinositide 3‐kinase (PI3K)–AKT signaling. (c) Epidermal growth factor (EGF) signaling. Ligand binding to ErbB receptors leads to homo‐ and heterodimerization, tyrosine autophosphorylation, and signaling through the MAPK and AKT pathways. ErbB2 does not bind EGF‐family ligands, and ErbB3 is catalytically inactive. (d) Transforming growth factor β (TGFβ) signaling. Ligand binding leads to heterodimerization of TGFβ receptor I (TGFβRI) and TGFβ receptor II (TGFβRII). TGFβRII transphosphorylates TGFβRI, which phosphorylates SMAD2/3 allowing them to heterodimerize with SMAD4 and translocate into the nucleus to modulate gene expression. (e) Wnt signaling. Ligand binding to the frizzled (Fz) receptor recruits the low‐density lipoprotein receptor‐related protein (LRP) coreceptor, which downregulates the β‐catenin destruction complex. This results in β‐catenin accumulation in the cytoplasm and its translocation to nucleus where it binds to T‐cell factor/lymphoid enhancer factor (TCF/LEF) and initiates transcription.

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Intercellular communication between adjacent epithelial cells via cell–cell signaling receptors. (a) E‐cadherin signaling. E‐cadherins form extracellular homophilic complexes between neighboring cells. p120 catenin binds to the juxtamembrane domain of E‐cadherin and stabilizes E‐cadherin by preventing clathrin‐mediated endocytosis. β‐catenin binds to E‐cadherin. α‐catenin shuttles between β‐catenin and epithelial protein lost in neoplasm (EPLIN), and connects the E‐cadherin complexes to F‐actin. (b) Delta‐Notch signaling. Notch binds to its ligand (Delta or Jagged) on adjacent cells, proteolytically releasing the Notch intracellular domain (NICD). NICD moves to the nucleus and interacts with DNA‐binding protein RBP (recombination signal‐binding protein for immunoglobulin kappa J region) along with several coactivators to regulate gene expression. Multiple Notch target genes, such as Hairy/enhancer of split (Hes) and lunatic fringe (Lfng), are negative regulators of the Notch pathway. These feedbacks can give rise to oscillations in gene expression. (c) Eph–ephrin signaling. Eph–ephrin binding on neighboring cells leads to bidirectional phosphotyrosine signaling. Eph‐expressing cells activate Eph RTK activity together with other tyrosine kinases, such as ABL, for each forward signaling. In ephrin‐expressing cells, other RTKs such as insulin‐like growth factor receptor (IGF1R) are transactivated. Ephrin‐induced reverse signaling is critical for boundary formation.

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A subset of the molecular and phenotypic heterogeneities among epithelia in the breast and small intestine. (a) Breast tissue contains an outer layer of myoepithelial cells and an inner layer of luminal epithelia. Stem/progenitor cells are distributed throughout the organ and multiple stem cells can contribute to branching morphogenesis. (b) The crypt–villus unit of the small intestine. Paneth cells lie at the bottom of the crypt. Stem cells located above paneth cells produce transit‐amplifying precursors that migrate and differentiate to enterocytes, enteroendocrine cells, goblet cells, or paneth cells.

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