DOCSLIB.ORG

The Crumbs3 Polarity Protein

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Crumbs3 Polarity Protein Downloaded from http://cshperspectives.cshlp.org/ on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press The Crumbs3 Polarity Protein Ben Margolis Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109-5680 Correspondence: [email protected] The Crumbs proteins are evolutionarily conserved apical transmembrane proteins. Drosophila Crumbs was discovered via its crucial role in epithelial polarity during fly em- bryogenesis. Crumbs proteins have variable extracellular domains but a highly conserved intracellular domain that can bind FERM and PDZ domain proteins. Mammals have three Crumbs genes and this review focuses on Crumbs3, the major Crumbs isoform expressed in mammalian epithelial cells. Although initial work has highlighted the role of Crumbs3 in polarity, more recent studies have found it has an important role in tissue morphogenesis functioning as a linker between the apical membrane and the actin cytoskeleton. In addi- tion, recent publications have linked Crumbs3 to growth control via regulation of the Hippo/ Yap pathway. pithelia polarize into apical and basolateral by mutual antagonism of apical and basolateral Emembranes with unique protein composi- protein complexes. In lower organisms, such as tions. This polarization is crucial for proper Drosophila, polarity is maintained solely by an- epithelial functions such as ion transport and tagonistic polarity complexes. In mammalian barrier protection. In mammalian epithelia, a cells, this biochemical polarization is further seal known as the tight junction separates the enforced by the tight junction seal (Shin et al. apical and basolateral membranes (Shin et al. 2006). There are two main evolutionarily con- 2006; Nelson 2009). The tight junction is com- served apical polarity complexes: the Crumbs posed of transmembrane proteins, primarily complex and the partitioning defective (Par) claudins that are organized by scaffold proteins complex (Pieczynski and Margolis 2011). The such as the zonula occludens. Another junc- Crumbs complex consists of three major pro- tion important for polarity is the adherens teins, Crumbs, protein associated with lin-7 one junction, which sits on the lateral membrane (Pals1; Stardust in Drosophila), and PALS1 as- basal to the tight junction. Its primary constit- sociated tight junction protein (Patj), all of uents are the cadherins. Adherens junctions are which are highly conserved from invertebrates mediators of cell–cell adhesion, a component to vertebrates. A similarly evolutionarily con- of polarity in epithelial sheets and tubes (Nel- served polarity complex is the Par complex son et al. 2013). that consists of Par3, Par6, and atypical protein Workover the last 20 years has indicated that kinase C (aPKC) (Pieczynski and Margolis apicobasal polarity is initiated and maintained 2011). aPKC is a crucial component of the apical Editor: Keith E. Mostov Additional Perspectives on Cell Polarity available at www.cshperspectives.org Copyright # 2017 Cold Spring Harbor Laboratory Press; all rights reserved Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a027961 1 Downloaded from http://cshperspectives.cshlp.org/ on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press B. Margolis polarity complex as phosphorylation is felt to brain, testis, uterus, eye, and embryonic tissue be the main biochemical effector mechanism (van den Hurk et al. 2005). Knockout of that results in membrane polarization. This re- Crumbs2 in mice results in embryonic lethality view will focus on the Crumbs complex and in at the late gastrulation stage (Xiao et al. 2011). particular the Crumbs3 protein, which is the Recent work has described patients with major Crumbs isoform found in mammalian Crumbs2 mutations resulting in ventriculo- epithelia. Although Crumbs was initially iden- megaly and nephrotic syndrome (Ebarasi et al. tified as a polarity protein, recent studies have 2015; Slavotinek et al. 2015). shown that it has multiple functions in epithe- The Crumbs3 gene is expressed in the ma- lial cells. jority of mammalian epithelia (Makarova et al. 2003). Crumbs3 exists in two variants as a result of alternate splicing of the final exon of the THE CRUMBS PROTEINS Crumbs3 gene. This alternate splicing results Crumbs was first identified in Drosophila as a in a 22–amino acid difference in the carboxyl regulator of epithelial polarity. In Drosophila terminus, altering the sequence of the PDZ- development, Crumbs is crucial for polariza- binding domain (Fan et al. 2007). Crumbs3a tion of the ectoderm that is formed after gas- has the carboxy-terminal sequence glutamic trulation. The external cuticle, which is derived acid–arginine–leucine–isoleucine(ERLI)ami- from this ectoderm, is disrupted when Crumbs no acids, which comprise its PDZ-binding mo- is not present leading to a speckled (crumbs- tif. Crumbs3b has a different carboxyl termi- like) appearance (Tepass et al. 1990). The nus, ending in the sequence cysteine–leucine– Drosophila Crumbs protein has a large extracel- proline–isoleucine (CLPI) that does not bind lular domain with 30 epidermal growth factor PDZ domains. The mechanisms regulating the (EGF)-like repeats, a single-span transmem- abundance of each splice variant are not yet brane region and a conserved cytoplasmic car- determined. The function of the Crumbs3 pro- boxyl terminus. The intracellular carboxyl ter- tein is discussed extensively below. minus contains a FERM (F for 4.1 protein, E for ezrin, R for radixin, and M for moesin)- CRUMBS-BINDING PARTNERS binding domain and a PDZ (P for postsynaptic density-95, D for discs large, and Z for zonula Crumbs binds to the conserved polarity pro- occludens1)-binding domain. In vertebrates, teins Pals1 (Drosophila Stardust) and Par6 via there are three Crumbs genes termed Crumbs1, its PDZ-binding carboxy-terminal sequence, Crumbs2, and Crumbs3. Crumbs1 and Crumbs2 ERLI (Fig. 1) (Hurd et al. 2003; Lemmers have large extracellular domains like the Dro- et al. 2004). Pals1/Stardust is a membrane- sophila Crumbs, whereas Crumbs3 has a very associated guanylate kinase (MAGUK) protein short extracellular domain (Makarova et al. with the core complex of PDZ, Src homology 2003). Crumbs1 is primarily localized to the domain 3 (SH3), and guanylate kinase domain retinal pigmented epithelium of the eye and (GUK) (Kamberov et al. 2000; Funke et al. mutations in the gene have been linked to reti- 2005). Loss-of-function of Pals1/Stardust in nal dystrophies (Alves et al. 2014). Many of Drosophila closely phenocopies loss of Crumbs these mutations are found in the extracellular (Bachmann et al. 2001; Hong et al. 2001). The domain of Crumbs1, which is consistent with complex of Crumbs3 bound to Pals1 has been the finding that mutations in the extracellular studied at a crystallographic level. Although the domain of Drosophila Crumbs leads to abnor- Crumbs3 ERLI carboxy-terminal sequence is mal photoreceptor morphogenesis in flies a classic PDZ-binding motif, these structural (Alves et al. 2014). Knockout of Crumbs1 in studies show that the PDZ, SH3, and GUK do- mice leads to photoreceptor degeneration after mains are all required for the high-affinity in- 9 months of age (van de Pavert et al. 2004). teraction between Crumbs3 and Pals1 (Li et al. Crumbs2 gene expression has been detected in 2014). The binding of Pals1 to Crumbs appears 2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a027961 Downloaded from http://cshperspectives.cshlp.org/ on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press The Crumbs3 Polarity Protein Crumbs3 Pals1 Par6 aPKC Lin-7 Par3 Patj Tight junction Claudins and JAMs Apical ZO-3 Lateral Lateral proteins Figure 1. Crumbs3 PDZ domain interactions. Through its carboxy-terminal tail (circle), Crumbs3 can bind two PDZ domain proteins, Pals1 (protein associated with lin-7 one) and Par6. Par6 can bind Par3 as well as atypical protein kinase C (aPKC), and aPKC can regulate basolateral polarity complexes via phosphorylation. Pals1 binds Patj (PALS1 associated tight junction protein) and Lin-7 via L27 domains. Patj has 10 PDZ domains that can mediate numerous interactions including to transmembrane tight junction proteins such as claudins and junctional adhesion molecules (JAMs), as well as to tight junction scaffolding proteins such as zonula occlu- dens 3 (ZO-3). to be of a much higher affinity than the binding as well as small G proteins such as Cdc42 (Pie- of Crumbs to Par6 (Whitney et al. 2016). At its czynski and Margolis 2011; Tepass 2012; Whit- amino terminus, Pals1 has two L27 domains ney et al. 2016). (Doerks et al. 2000). One of these L27 domains Several proteins have also been identified binds to the small PDZ scaffold protein Lin-7 that bind to the Crumbs FERM-binding do- (Kamberov et al. 2000). The other L27 domains main (Fig. 2). Yurt was shown to bind the bind the multi-PDZ domain proteins, Patj and FERM-binding domain of Drosophila Crumbs multiple PDZ domain protein 1 (Mupp1) (Roh and function as a negative regulator of Crumbs et al. 2002; Assemat et al. 2013). Patj has multi- (Laprise et al. 2006). Studies have also indicated ple PDZ domains and can connect the Crumbs3 that the mammalian orthologs of Yurt, YMO1, complex to proteins of the tight junction such EHM2, and EPB41L5 have a similar function in as the zonula occludens proteins (Adachi et al. mammalian cells and form a novel complex 2009). The nature and extent of the interaction with Crumbs3 and Pals1 (Laprise et al. 2006, of the Par complex with the Crumbs complex 2009; Gosens et al. 2007). In Drosophila varies depending on the epithelia in which it is Crumbs, the FERM-binding domain interacts studied. There are multiple regulatory factors with the expanded protein to regulate growth that control these interactions, including aPKC control (see below) (Grzeschik et al. 2010; Ling Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a027961 3 Downloaded from http://cshperspectives.cshlp.org/ on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press B.
Load more

Recommended publications
  • Epithelia and Gastrointestinal Function
    CHAPTER 18 Epithelia and gastrointestinal function Jerrold R. Turner University of Chicago, Chicago, IL, USA Chapter menu Organization of the gut wall, 317 Epithelial barrier and disease , 326 Organization of epithelial cells and sheets, 318 Integration of mucosal function, 329 Mucosal barriers, 322 Further reading, 329 All cavities within the alimentary tract, from the small ducts An underlying layer of fibroconnective tissue called the sub- and acini of the pancreas to the gastric lumen, are lined by mucosa, which contains nerves, vessels, and lymphatics, sup- sheets of polarized epithelial cells. Common to all of these epi- ports the mucosa. The submucosa rests on the muscularis thelia is the ability to create selective barriers that separate propria, which is composed of two or three layers of smooth luminal and tissue spaces. Most epithelia are also able to direct muscle and is home to the myenteric plexus (see Chapters 1, 15, vectorial transport of solutes and solvents. These essential func- and 16). In most instances, gastrointestinal organs are encased tions are based on the structural polarity of individual cells, the by an outermost delicate layer of fibrofatty tissue, the serosa, complex organization of membranes, cell–cell and cell–substrate encircled by a continuous layer of mesothelial cells. In areas interactions, and interactions with other cell types. This chapter where no serosa exists, as in portions of the esophagus and the reviews intestinal wall structure and examines how mucosal distal colorectum, fibrofatty tissues interface with the external functions are supported by the organization of the gut and the portion of the muscularis propria.
    [Show full text]
  • EGF Shifts Human Airway Basal Cell Fate Toward a Smoking-Associated Airway Epithelial Phenotype
    EGF shifts human airway basal cell fate toward a smoking-associated airway epithelial phenotype Renat Shaykhiev1, Wu-Lin Zuo1, IonWa Chao, Tomoya Fukui, Bradley Witover, Angelika Brekman, and Ronald G. Crystal2 Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065 Edited* by Michael J. Welsh, Howard Hughes Medical Institute, Iowa City, IA, and approved May 29, 2013 (received for review February 19, 2013) The airway epithelium of smokers acquires pathological phenotypes, phosphorylation, indicative of EGFR receptor activation, has including basal cell (BC) and/or goblet cell hyperplasia, squamous been observed in airway epithelial cells exposed to cigarette metaplasia, structural and functional abnormalities of ciliated cells, smoke in vitro (26, 27). decreased number of secretoglobin (SCGB1A1)-expressing secretory Based on this knowledge, we hypothesized that smoking- cells, and a disordered junctional barrier. In this study, we hypoth- induced changes in the EGFR pathway are relevant to the EGFR- fi esized that smoking alters airway epithelial structure through dependent modi cation of BCs toward the abnormal differentia- modification of BC function via an EGF receptor (EGFR)-mediated tion phenotypes present in the airway epithelium of smokers. mechanism. Analysis of the airway epithelium revealed that EGFR is In this study, we provide evidence that although EGFR is ex- pressed predominantly in BCs, smoking induces expression of enriched in airway BCs, whereas its ligand EGF is induced by smoking EGF in ciliated
    [Show full text]
  • A Novel PLEKHA7 Interactor at Adherens Junctions
    Thesis PDZD11: a novel PLEKHA7 interactor at adherens junctions GUERRERA, Diego Abstract PLEKHA7 is a recently identified protein of the AJ that has been involved by genetic and genomic studies in the regulation of miRNA signaling and cardiac contractility, hypertension and glaucoma. However, the molecular mechanisms behind PLEKHA7 involvement in tissue physiology and pathology remain unknown. In my thesis I report novel results which uncover PLEKHA7 functions in epithelial and endothelial cells, through the identification of a novel molecular interactor of PLEKHA7, PDZD11, by yeast two-hybrid screening, mass spectrometry, co-immunoprecipitation and pulldown assays. I dissected the structural basis of their interaction, showing that the WW domain of PLEKHA7 binds to the N-terminal region of PDZD11; this interaction mediates the junctional recruitment of PDZD11, identifying PDZD11 as a novel AJ protein. I provided evidence that PDZD11 forms a complex with nectins at AJ, its PDZ domain binds to the PDZ-binding motif of nectins. PDZD11 stabilizes nectins promoting the early steps of junction assembly. Reference GUERRERA, Diego. PDZD11: a novel PLEKHA7 interactor at adherens junctions. Thèse de doctorat : Univ. Genève, 2016, no. Sc. 4962 URN : urn:nbn:ch:unige-877543 DOI : 10.13097/archive-ouverte/unige:87754 Available at: http://archive-ouverte.unige.ch/unige:87754 Disclaimer: layout of this document may differ from the published version. 1 / 1 UNIVERSITE DE GENÈVE FACULTE DES SCIENCES Section de Biologie Prof. Sandra Citi Département de Biologie Cellulaire PDZD11: a novel PLEKHA7 interactor at adherens junctions THÈSE Présentée à la Faculté des sciences de l’Université de Genève Pour obtenir le grade de Doctor ès science, mention Biologie par DIEGO GUERRERA de Benevento (Italie) Thèse N° 4962 GENÈVE Atelier d'impression Repromail 2016 1 Table of contents RÉSUMÉ ..................................................................................................................
    [Show full text]
  • Cell and Tissue Polarity As a Non-Canonical Tumor Suppressor
    Commentary 1141 Cell polarity and cancer – cell and tissue polarity as a non-canonical tumor suppressor Minhui Lee1,2 and Valeri Vasioukhin1,3,* 1Division of Human Biology, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N., C3-168, Seattle, WA 98109, USA 2Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98109, USA 3Department of Pathology and Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98195, USA *Author for correspondence (e-mail: [email protected]) Accepted 19 February 2008 Journal of Cell Science 121, 1141-1150 Published by The Company of Biologists 2008 doi:10.1242/jcs.016634 Summary Correct establishment and maintenance of cell polarity is and differentiation of cancer stem cells. Data from in vivo and required for the development and homeostasis of all three-dimensional (3D) cell-culture models demonstrate that metazoans. Cell-polarity mechanisms are responsible not only tissue organization attenuates the phenotypic outcome of for the diversification of cell shapes but also for regulation of oncogenic signaling. We suggest that polarized 3D tissue the asymmetric cell divisions of stem cells that are crucial for organization uses cell-cell and cell-substratum adhesion their correct self-renewal and differentiation. Disruption of cell structures to reinforce and maintain the cell polarity of pre- polarity is a hallmark of cancer. Furthermore, recent evidence cancerous cells. In this model, polarized 3D tissue organization indicates that loss of cell polarity is intimately involved in functions as a non-canonical tumor suppressor that prevents cancer: several crucial cell-polarity proteins are known proto- the manifestation of neoplastic features in mutant cells and, oncogenes or tumor suppressors, basic mechanisms of cell ultimately, suppresses tumor development and progression.
    [Show full text]
  • 2003 Cell Bio Gibson.Pdf
    747 Apicobasal polarization: epithelial form and function Matthew C Gibson and Norbert Perrimonà The structure and function of epithelial sheets generally depend (Figure 1a). Contrasting with Drosophila, vertebrate on apicobasal polarization, which is achieved and maintained by epithelial cells lack SJs and instead exhibit tight junctions linking asymmetrically distributed intercellular junctions to the (TJs), cell–cell adhesive structures that lie apical to the cytoskeleton of individual cells. Recent studies in both vertebrate ZA in a position analogous to the Drosophila Drosophila and vertebrate epithelia have yielded new insights SAR [2] (Figure 1b). The apical TJ complexes between into the conserved mechanisms by which apicobasal polarity is vertebrate epithelial cells serve an organizing role in established and maintained during development. In mature epithelial polarization and establish a paracellular diffu- polarized epithelia, apicobasal polarity is important for the sion barrier that restricts the movement of solutes across establishment of adhesive junctions and the formation of a the cell layer [4,5]. This barrier effectively segregates the paracellular diffusion barrier that prevents the movement of epithelium and surrounding media into immiscible apical solutes across the epithelium. Recent findings show that and basolateral compartments. In Drosophila, SJs appear segregation of ligand and receptor with one on each side of this to fulfill a similar paracellular barrier role to the vertebrate barrier can be a crucial regulator of cell–cell signaling events. TJs [6,7], albeit with the functional barrier lying basal to the ZA. Addresses Department of Genetics, Harvard Medical School, 200 Longwood Despite differences in the distribution of cell–cell junc- Avenue, Boston MA, 02115, USA tions, conserved sets of polarity proteins govern api- Ãe-mail: [email protected] cobasal polarization in both Drosophila and vertebrate epithelia.
    [Show full text]
  • Deciphering the Mechanoresponsive Role of Β-Catenin in Keratoconus
    bioRxiv preprint doi: https://doi.org/10.1101/603738; this version posted April 9, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 Deciphering the mechanoresponsive role of β-catenin in Keratoconus 2 epithelium 3 4 Chatterjee Amit 1,2, Prema Padmanabhan3, Janakiraman Narayanan#1 5 1 Department of Nanobiotechnology, Vision Research Foundation,Sankara Nethralaya campus, 6 Chennai, Tamil Nadu, India 7 2 School of Chemical and Biotechnology, SASTRA University, Tanjore, Tamil Nadu, India 8 3 Department of Cornea, Medical Research Foundation, Sankara Nethralaya campus, Chennai, 9 Tamil Nadu ,India 10 Running Title: β-catenin mechanotransduction in kerataconus 11 Correspondence: #Dr. Janakiraman Narayanan, Department of Nanobiotechnology, KNBIRVO 12 Block, Vision Research Foundation, Sankara Nethralaya campus 18/41, College road 13 Nungambakkam, Chennai, Tamil Nadu, India 600006, Tel-+91-44-28271616, (Ext) 1358, Fax- 14 +91-44-28254180, Email: [email protected] 15 16 17 18 19 20 21 22 23 1 bioRxiv preprint doi: https://doi.org/10.1101/603738; this version posted April 9, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 24 25 Abstract 26 Keratoconus (KC) a disease with established biomechanical instability of the corneal stroma, is an 27 ideal platform to identify key proteins involved in mechanosensing.
    [Show full text]
  • A Fence Function for Adherens Junctions in Epithelial Cell Polarity
    bioRxiv preprint doi: https://doi.org/10.1101/605808; this version posted April 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. A fence function for adherens junctions in epithelial cell polarity Mario Aguilar-Aragon, Alex Tournier & Barry J Thompson* The Francis Crick Institute, 1 Brill Place, St Pancras, NW1 1BF, London, United Kingdom. * [email protected]; @thompsonlab Word count: 3,500 Figures: 4 1 bioRxiv preprint doi: https://doi.org/10.1101/605808; this version posted April 11, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Abstract Adherens junctions are a defining feature of all epithelial cells, providing cell- cell adhesion and being essential for cell and tissue morphology. In Drosophila, adherens junctions are concentrated between the apical and basolateral plasma membrane domains, but whether they contribute to apical- basal polarisation itself has been unclear. Here we show that, in the absence of adherens junctions, apical-basal polarity determinants can still segregate into complementary domains, but control of apical versus basolateral domain size is lost. Manipulation of the level of apical or basal polarity determinants in experiments and in computer simulations suggests that junctions provide a moveable diffusion barrier, or fence, that restricts the diffusion of polarity determinants to enable precise domain size control.
    [Show full text]
  • HHS Public Access Author Manuscript
    HHS Public Access Author manuscript Author Manuscript Author ManuscriptFertil Steril Author Manuscript. Author manuscript; Author Manuscript available in PMC 2017 February 01. Published in final edited form as: Fertil Steril. 2016 February ; 105(2): 501–510.e1. doi:10.1016/j.fertnstert.2015.10.011. Cryopreservation and Recovery of Human Endometrial Epithelial Cells with High Viability, Purity, and Functional Fidelity Joseph C. Chen, PhD, MSa, Jacquelyn R. Hoffman, BAa, Ripla Arora, PhD, MSa, Lila A. Perronea, Christian J Gonzalez-Gomeza, Kim Chi Vo, BSa, Diana J. Laird, PhDa, Juan C. Irwin, MD, PhDa, and Linda C. Giudice, MD, PhDa aCenter for Reproductive Sciences, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco Abstract Objective—To develop a protocol for cryopreservation and recovery of human endometrial epithelial cells (eEC) retaining molecular and functional characteristics of endometrial epithelium in vivo. Design—This is an in vitro study using human endometrial cells. Setting—University research laboratory. Patients—Endometrial biopsies were obtained from premenopausal women undergoing benign gynecological procedures. Interventions—Primary eEC were cryopreserved in 1% fetal bovine serum (FBS)/10% dimethyl sulfoxide (DMSO) in Defined Keratinocyte Serum Free Medium (KSFM). Recovered cells were observed for endometrial stromal fibroblast (eSF) contamination and subsequently evaluated for morphology, gene expression, and functional characteristics of freshly cultured eECs and in vivo endometrial epithelium. Main Outcome Measures—Analysis of eEC morphology and the absence of eSF contamination; evaluation of epithelial-specific gene and protein expression; assessment of epithelial polarity. Results—eEC recovered after cryopreservation (n=5) displayed epithelial morphology and expressed E-cadherin (CDH1), occludin (OCLN), claudin1 (CLDN1), and keratin18 (KRT18).
    [Show full text]
  • A Common Framework for EMT and Collective Cell Migration Kyra Campbell1,2,* and Jordi Casanova1,2,*
    © 2016. Published by The Company of Biologists Ltd | Development (2016) 143, 4291-4300 doi:10.1242/dev.139071 HYPOTHESIS A common framework for EMT and collective cell migration Kyra Campbell1,2,* and Jordi Casanova1,2,* ABSTRACT occur during animal development tend to escape from the simplicity During development, cells often switch between static and migratory of these definitions. First, not only do many intermediate situations behaviours. Such transitions are fundamental events in development exist, with migrating cells possessing a combination of epithelial and are linked to harmful consequences in pathology. It has long and mesenchymal features, but it is evident that these are far more been considered that epithelial cells either migrate collectively as commonly seen in vivo than previously thought (Nakaya and Sheng, epithelial cells, or undergo an epithelial-to-mesenchymal transition 2008; Shook and Keller, 2003). Second, it is now clear that and migrate as individual mesenchymal cells. Here, we assess what mesenchymal cells often migrate exhibiting the coordination and is currently known about in vivo cell migratory phenomena and cooperation ascribed to collectively migrating cells (Scarpa and hypothesise that such migratory behaviours do not fit into alternative Mayor, 2016; Theveneau and Mayor, 2011). To cope with these and mutually exclusive categories. Rather, we propose that these observations, distinctions between individual and collective cell categories can be viewed as the most extreme cases of a general migration have evolved from very strict to more inclusive or loose continuum of morphological variety, with cells harbouring different definitions (Rørth, 2012; Theveneau and Mayor, 2011). degrees or combinations of epithelial and mesenchymal features and Accordingly, any attempts to classify migratory events and thus displaying an array of migratory behaviours.
    [Show full text]
  • Functional Restoration of Irradiated Salivary Glands Through Modulation of Apkcζ and Nuclear Yap in Salivary Progenitors
    Functional Restoration of Irradiated Salivary Glands Through Modulation of aPKCζ and Nuclear Yap in Salivary Progenitors Item Type text; Electronic Dissertation Authors Martinez Chibly, Agustin Alejandro Publisher The University of Arizona. Rights Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. Download date 11/10/2021 05:49:05 Link to Item http://hdl.handle.net/10150/621771 FUNCTIONAL RESTORATION OF IRRADIATED SALIVARY GLANDS THROUGH MODULATION OF APKC AND NUCLEAR YAP IN SALIVARY PROGENITORS by Agustin Alejandro Martinez Chibly ___________________________________________ Copyright © Agustin Alejandro Martinez Chibly 2016 A Dissertation Submitted to the Faculty of the THE GRADUATE INTERDISCIPLINARY PROGRAM IN CANCER BIOLOGY In Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY In the Graduate College THE UNIVERSITY OF ARIZONA 2016 2 THE UNIVERSITY OF ARIZONA GRADUATE COLLEGE As members of the Dissertation Committee, we certify that we have read the dissertation prepared by Agustin Alejandro Martinez Chibly entitled “Functional Restoration of Irradiated Salivary Glands Through Modulation of aPKC and nuclear Yap in Salivary Progenitors” and recommend that it be accepted as fulfilling the dissertation requirement for the Degree of Doctor of Philosophy _______________________________________________________________________
    [Show full text]
  • Case Studies in Cholera: Lessons in Medical History and Science
    YALE JOURNAL OF BIOLOGY AND MEDICINE 72 (1999), pp. 393-408. Copyright C) 2000. All rights reserved. MEDICAL REVIEW Case Studies in Cholera: Lessons in Medical History and Science Stephen M. Kavica, Eric J. Frehmb, and Alan S. Segalc aDepartment of Surgery, Yale University School of Medicine, New Haven, Connecticut; bDepartment of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania; and CDepartments of Medicine, Molecular Physiology and Biophysics, and Pharmacology, University of Vermont, Burlington, Vermont Cholera, a prototypical secretory diarrheal disease, is an ancient scourge that has both wrought great suffering and taught many valuable lessons, from basic sanitation to molecular signal trans- duction. Victims experience the voluminous loss of bicarbonate-rich isotonic saline at a rate that may lead to hypovolemic shock, metabolic acidosis, and death within afew hours. Intravenous solu- tion therapy as we know it wasfirst developed in an attempt to provide life-saving volume replace- mentfor cholera patients. Breakthroughs in epithelial membrane transport physiology, such as the discovery ofsugar and salt cotransport, have paved the wayfor oral replacement therapy in areas of the world where intravenous replacement is not readily available. In addition, the discovery of the cholera toxin has yielded vital information about toxigenic infectious diseases, providing a framework in which to study fundamental elements of intracellular signal transduction pathways, such as G-proteins. Cholera may even shed light on the evolution and pathophysiology of cystic fibrosis, the most commonly inherited disease among Caucasians. The goal of this paper is to review, using case studies, some of the lessons learned from cholera throughout the ages, acknowledging those pioneers whose seminal work led to our understanding ofmany basic concepts in medical epidemiology, microbiology, physiology, and therapeuticsf INTRODUCTION a short, curved, bacterium that produces an enterotoxin (choleragen).
    [Show full text]
  • Epithelial Cell Polarity and Cell Junctions in Drosophila
    18 Oct 2001 10:14 AR AR144-24.tex AR144-24.sgm ARv2(2001/05/10) P1: GJB Annu. Rev. Genet. 2001. 35:747–84 Copyright c 2001 by Annual Reviews. All rights reserved EPITHELIAL CELL POLARITY AND CELL JUNCTIONS IN DROSOPHILA Ulrich Tepass and Guy Tanentzapf Department of Zoology, University of Toronto, 25 Harbord Street, Toronto, Ontario M5S3G5, Canada; e-mail: [email protected], [email protected] Robert Ward and Richard Fehon DCMB Group, Department of Biology, Duke University, B333 LSRC Research Drive, Durham, North Carolina 27708; e-mail: [email protected]; [email protected] Key Words epithelium, polarity, cellular junctions, cellularization, membrane domain ■ Abstract The polarized architecture of epithelial cells and tissues is a fundamen- tal determinant of animal anatomy and physiology. Recent progress made in the genetic and molecular analysis of epithelial polarity and cellular junctions in Drosophila has led to the most detailed understanding of these processes in a whole animal model system to date. Asymmetry of the plasma membrane and the differentiation of membrane do- mains and cellular junctions are controlled by protein complexes that assemble around transmembrane proteins such as DE-cadherin, Crumbs, and Neurexin IV, or other cy- toplasmic protein complexes that associate with the plasma membrane. Much remains to be learned of how these complexes assemble, establish their polarized distribution, and contribute to the asymmetric organization of epithelial cells. CONTENTS INTRODUCTION .....................................................748
    [Show full text]