title: Defective goblet cell exocytosis contributes to murine cystic fibrosis-associated intestinal disease.
abstract: Cystic fibrosis (CF) intestinal disease is associated with the pathological manifestation mucoviscidosis, which is the secretion of tenacious, viscid mucus that plugs ducts and glands of epithelial-lined organs. Goblet cells are the principal cell type involved in exocytosis of mucin granules; however, little is known about the exocytotic process of goblet cells in the CF intestine. Using intestinal organoids from a CF mouse model, we determined that CF goblet cells have altered exocytotic dynamics, which involved intrathecal granule swelling that was abruptly followed by incomplete release of partially decondensated mucus. Some CF goblet cells exhibited an ectopic granule location and distorted cellular morphology, a phenotype that is consistent with retrograde intracellular granule movement during exocytosis. Increasing the luminal concentration of bicarbonate, which mimics CF transmembrane conductance regulator-mediated anion secretion, increased spontaneous degranulation in WT goblet cells and improved exocytotic dynamics in CF goblet cells; however, there was still an apparent incoordination between granule decondensation and exocytosis in the CF goblet cells. Compared with those within WT goblet cells, mucin granules within CF goblet cells had an alkaline pH, which may adversely affect the polyionic composition of the mucins. Together, these findings indicate that goblet cell dysfunction is an epithelial-autonomous defect in the CF intestine that likely contributes to the pathology of mucoviscidosis and the intestinal manifestations of obstruction and inflammation.
authors: Jinghua
authors: J
authors: Liu
authors: Nancy M
authors: NM
authors: Walker
authors: Akifumi
authors: A
authors: Ootani
authors: Ashlee M
authors: AM
authors: Strubberg
authors: Lane L
authors: LL
authors: Clarke
mesh_terms: D000818:Animals; D003550:Cystic Fibrosis / Q000473:pathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D005089:Exocytosis; D020397:Goblet Cells / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D007413:Intestinal Mucosa / Q000473:pathology; D018345:Mice, Knockout; D009077:Mucins / Q000378:metabolism; D022142:Secretory Vesicles / Q000378:metabolism
chemical_list: D009077:Mucins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
references: J Cell Sci Suppl. 1993;17:229-33
references: 7511615
references: Am Rev Respir Dis. 1991 Sep;144(3 Pt 2):S33-7
references: 1892323
references: Respir Med. 2002 Feb;96(2):81-6
references: 11860173
references: Drugs R D. 2006;7(1):17-31
references: 16620134
references: Am J Physiol Cell Physiol. 2012 Jul 15;303(2):C160-9
references: 22572847
references: J Biol Chem. 2003 Apr 18;278(16):13944-51
references: 12582180
references: Gastroenterology. 2003 Oct;125(4):1148-63
references: 14517798
references: Proc Natl Acad Sci U S A. 2012 Apr 10;109(15):5645-50
references: 22451922
references: Am J Physiol Gastrointest Liver Physiol. 2004 Aug;287(2):G480-90
references: 15064229
references: Physiol Rev. 2003 Apr;83(2):581-632
references: 12663867
references: Exp Cell Res. 2005 Oct 1;309(2):296-304
references: 16051214
references: Am J Physiol. 1997 Aug;273(2 Pt 1):G258-66
references: 9277402
references: J Clin Invest. 1989 Jul;84(1):68-72
references: 2738159
references: J Neurosci. 1999 Feb 1;19(3):900-5
references: 9920653
references: Nature. 1991 Jul 4;352(6330):70-3
references: 1712081
references: Biochem Biophys Res Commun. 1992 Apr 15;184(1):300-5
references: 1373612
references: Am J Physiol Gastrointest Liver Physiol. 2007 Sep;293(3):G577-84
references: 17615175
references: Am J Physiol Gastrointest Liver Physiol. 2006 Dec;291(6):G1148-54
references: 16825704
references: J Biol Chem. 2006 Feb 24;281(8):4844-55
references: 16377632
references: J Biol Chem. 2005 Apr 29;280(17):16868-81
references: 15718243
references: J Pediatr Surg. 2012 Apr;47(4):772-81
references: 22498395
references: Am J Respir Crit Care Med. 2006 Nov 1;174(9):1018-24
references: 16917116
references: Novartis Found Symp. 2002;248:132-41; discussion 141-9, 277-82
references: 12568492
references: Pediatr Res. 2000 Mar;47(3):344-50
references: 10709733
references: Arch Histol Cytol. 2005;68(1):51-6
references: 15827378
references: Biochim Biophys Acta. 2005 Dec 20;1719(1-2):82-101
references: 16359942
references: J Biol Chem. 1996 Jun 28;271(26):15542-8
references: 8663158
references: Infect Immun. 2004 Oct;72(10):6040-9
references: 15385508
references: Science. 1981 Feb 13;211(4483):712-5
references: 6779379
references: Proc Natl Acad Sci U S A. 2014 Aug 26;111(34):12396-401
references: 25114233
references: Cold Spring Harb Perspect Med. 2012 Nov;2(11). pii: a009597. doi: 10.1101/cshperspect.a009597
references: 23125200
references: J Clin Invest. 1999 Jun;103(12):1677-84
references: 10377174
references: Am J Physiol Cell Physiol. 2000 Jan;278(1):C212-33
references: 10644530
references: J Clin Invest. 2009 Sep;119(9):2613-22
references: 19726884
references: J Cell Biol. 2013 Oct 28;203(2):283-98
references: 24165939
references: Am J Physiol Gastrointest Liver Physiol. 2004 Jun;286(6):G1050-8
references: 14715526
references: Science. 1992 May 8;256(5058):774-9
references: 1375392
references: Science. 2014 Aug 15;345(6198):818-22
references: 25124441
references: Gastroenterology. 2000 Jun;118(6):1051-60
references: 10833480
references: Am J Respir Cell Mol Biol. 2011 Jan;44(1):83-90
references: 20203293
references: J Pediatr Gastroenterol Nutr. 2005 Sep;41(3):273-85
references: 16131979
references: Nat Cell Biol. 2006 Sep;8(9):933-44
references: 16921366
references: J Clin Invest. 2010 May;120(5):1722-35
references: 20407206
references: Am J Physiol Gastrointest Liver Physiol. 2007 Jul;293(1):G222-9
references: 17615178
references: Am J Physiol Cell Physiol. 2012 May 15;302(10):C1492-503
references: 22403785
references: FASEB J. 2011 Dec;25(12):4274-91
references: 21873556
references: Pediatr Res. 1998 Feb;43(2):234-9
references: 9475290
references: Am J Pathol. 2010 Mar;176(3):1377-89
references: 20110417
references: Am J Physiol Gastrointest Liver Physiol. 2004 Jun;286(6):G1032-41
references: 14739145
references: Lab Anim Sci. 1996 Dec;46(6):612-8
references: 9001172
references: Science. 1992 Aug 21;257(5073):1083-8
references: 1380723
references: Am J Respir Cell Mol Biol. 1993 Sep;9(3):315-22
references: 8398169
references: J Exp Biol. 1992 Nov;172:245-66
references: 1337094
references: Annu Rev Physiol. 2008;70:487-512
references: 17988208
references: Front Pharmacol. 2011 Oct 25;2:67
references: 22046162
references: Am J Physiol Gastrointest Liver Physiol. 2005 Jun;288(6):G1241-51
references: 15650130
references: Mol Biol Cell. 2005 May;16(5):2154-67
references: 15716351
references: Am J Physiol. 1997 Apr;272(4 Pt 1):G872-8
references: 9142920
references: Chem Biol. 1999 Jul;6(7):411-8
references: 10381401
references: J Neurochem. 2006 Jan;96(2):324-34
references: 16336635
references: Am J Physiol Gastrointest Liver Physiol. 2010 Aug;299(2):G381-90
references: 20522639
references: Arch Dis Child. 2000 May;82(5):394-9
references: 10799435
references: Nature. 2009 May 14;459(7244):262-5
references: 19329995
references: Am J Physiol Gastrointest Liver Physiol. 2013 Jul 15;305(2):G151-62
references: 23660502
references: J Clin Invest. 1999 May 15;103(10):1379-89
references: 10330420
references: Hum Gene Ther. 1998 Mar 20;9(5):635-48
references: 9551612
references: Cold Spring Harb Perspect Med. 2012 Sep;2(9):a009589
references: 22951447
references: Am J Respir Cell Mol Biol. 2013 Oct;49(4):511-6
references: 23742042
references: Eur Respir J. 2003 Dec;22(6):972-9
references: 14680088
references: J Histochem Cytochem. 1996 Oct;44(10):1161-6
references: 8813081
references: Glycobiology. 2000 Feb;10(2):149-57
references: 10642606
references: Nature. 2012 Mar 15;483(7389):345-9
references: 22422267
references: Am J Physiol Gastrointest Liver Physiol. 2012 Feb 15;302(4):G430-8
references: 22159279
references: Prog Histochem Cytochem. 1997;31(4):1-78
references: 9088045
references: J Biol Chem. 2009 Mar 20;284(12):7681-6
references: 19136560
references: J Exp Med. 2012 Jul 2;209(7):1263-72
references: 22711878
references: Proc Natl Acad Sci U S A. 2012 Dec 18;109(51):E3539-48
references: 23184982
references: Gastroenterology. 2004 Jan;126(1):32-41
references: 14699484
references: ScientificWorldJournal. 2012;2012:465230
references: 22645424
references: Biochim Biophys Acta. 2011 Nov;1812(11):1385-92
references: 21907281