Differentiation of columnar epithelia: the hensin pathway
ABSTRACT Epithelia, the most common variety of cells in complex organisms exist in many shapes. They are sheets of polarized cells that separate two compartments and selectively transport materials from one to the other. After acquiring these general characteristics, they differentiate to become specialized types such as squamous columnar or transitional epithelia. High density seeding converts a kidney-derived cell line from flat ;generic' epithelial cells to columnar cells. The cells acquire all the characteristics of differentiated columnar cells, including microvilli, and the capacity for apical endocytosis. The high seeding density induces the deposition of a new protein termed hensin and polymerization of hensin is the crucial event that dictates changes in epithelial phenotype. Hensin is widely expressed in most epithelia. Its deletion in mice leads to embryonic lethality at the time of generation of the first columnar epithelium, the visceral endoderm. Moreover many human cancers have deletions in the hensin gene, which indicates that it is a tumor suppressor.
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ABSTRACT: The Dmbt1 gene encodes alternatively spliced glycoproteins that are either membrane-associated or secreted epithelial products. Functions proposed for Dmbt1 include it being a tumor suppressor, having roles in innate immune defense and inflammation, and being a Golgi-sorting receptor in the exocrine pancreas. The heavily sulfated membrane glycoprotein mucin-like glycoprotein (Muclin) is a Dmbt1 product that is strongly expressed in organs of the gastrointestinal (GI) system. To explore Muclin's functions in the GI system, the Dmbt1 gene was targeted to produce Muclin-deficient mice. Muclin-deficient mice have normal body weight gain and are fertile. The Muclin-deficient mice did not develop GI tumors, even when crossed with mice lacking the known tumor suppressor p53. When colitis was induced by dextran sulfate sodium, there was no significant difference in disease severity in Muclin-deficient mice. Also, when acute pancreatitis was induced with supraphysiological caerulein, there was no difference in disease severity in the Muclin-deficient mice. Exocrine pancreatic function was impaired, as measured by attenuated neurohormonal-stimulated amylase release from Muclin-deficient acinar cells. Also, by [(35)S]Met/Cys pulse-chase analysis, traffic of newly synthesized protein to the stimulus-releasable pool was significantly retarded in Muclin-deficient cells compared with wild type. Thus Muclin deficiency impairs trafficking of regulated proteins to a stimulus-releasable pool in the exocrine pancreas.AJP Gastrointestinal and Liver Physiology 04/2008; 294(3):G717-27. DOI:10.1152/ajpgi.00525.2007 · 3.74 Impact Factor
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ABSTRACT: Epithelial differentiation proceeds in at least two steps: Conversion of a nonepithelial cell into an epithelial sheet followed by terminal differentiation into the mature epithelial phenotype. It was recently discovered that the extracellular matrix (ECM) protein hensin is able to convert a renal intercalated cell line from a flat, squamous shape into a cuboidal or columnar epithelium. Global knockout of hensin in mice results in embryonic lethality at the time that the first columnar cells appear. Here, antibodies that either activate or block integrin beta1 were used to demonstrate that activation of integrin alpha v beta 1 causes deposition of hensin in the ECM. Once hensin polymerizes and deposits into the ECM, it binds to integrin alpha 6 and mediates the conversion of epithelial cells to a cuboidal phenotype capable of apical endocytosis; therefore, multiple integrins play a role in the terminal differentiation of the intercalated cell: alpha v beta 1 generates polymerized hensin, and another set of integrins (containing alpha 6) mediates signals between hensin and the interior of the cells.Journal of the American Society of Nephrology 07/2008; 19(6):1079-91. DOI:10.1681/ASN.2007070737 · 9.47 Impact Factor
Article: Dry eye and designer ophthalmics[Show abstract] [Hide abstract]
ABSTRACT: Expressed sequence tag (EST), proteomic, and antibody capture assays are revealing a level of tear film protein complexity far greater than previously appreciated. A systems biology approach will be needed to fully appreciate function as tear protein doses fluctuate in time through different conditions. Although consensus is growing on what fully constitutes the human tear proteome, questions remain about the source and significance of the approximately 256 tear proteins designated as "intracellular." Many of these may derive from normal cellular turnover and could therefore be informative. A further >183 are designated as "extracellular." Surprisingly, only 4 to 5% of these appear to be dysregulated in the three forms of dry eye preliminarily examined to date. Some differ and a couple overlap, suggesting that disease-specific signatures could be identified. Future dry eye treatment might include recombinant tear protein rescue as a personalized ophthalmic approach to ocular surface disease.Optometry and Vision Science 08/2008; 85(8):643-52. DOI:10.1097/OPX.0b013e318181ae73 · 2.04 Impact Factor