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The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1998 Nov 15;102(10):1798–1806. doi: 10.1172/JCI3820

Cystic fibrosis mice lacking Muc1 have reduced amounts of intestinal mucus.

R R Parmley 1, S J Gendler 1
PMCID: PMC509129  PMID: 9819365

Abstract

Normally a thin layer of mucus covers the surface of the gastrointestinal tract protecting the epithelial cells from their environment. In cystic fibrosis (CF), mucus accumulation is abnormally high, resulting in severe intestinal obstruction. The major structural components of mucus are large mucin glycoproteins. We determined specific mucin RNA and protein expression in the gastrointestinal tract of inbred CF transmembrane conductance regulator (CFTR) knockout (CF) mice and correlated expression with histological analyses of tissues. Mucins were detected histochemically using general carbohydrate stains and specific mucin antibodies. Mucin RNA levels were determined by reverse transcription-PCR. Comparisons were made between CF mice and control siblings, all maintained on a liquid diet after weaning. Analyses of the mucins Muc2, Muc3, and Muc5ac showed lower levels of RNA expression in the CF mice and similar levels of protein. Significantly, there was a sixfold increase in Muc1 RNA expression in the colon of the CF mouse and a moderate increase in Muc1 protein. Further, CF mice lacking Muc1 exhibited greatly diminished intestinal mucus obstruction when compared with Muc1- expressing CF mice and had better survival on solid food. We suggest that Muc1 plays an important role in the mucus obstructions observed in the gastrointestinal tract of the CFTR knockout mouse.

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Selected References

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  1. Alonso S., Minty A., Bourlet Y., Buckingham M. Comparison of three actin-coding sequences in the mouse; evolutionary relationships between the actin genes of warm-blooded vertebrates. J Mol Evol. 1986;23(1):11–22. doi: 10.1007/BF02100994. [DOI] [PubMed] [Google Scholar]
  2. Baeckström D., Hansson G. C., Nilsson O., Johansson C., Gendler S. J., Lindholm L. Purification and characterization of a membrane-bound and a secreted mucin-type glycoprotein carrying the carcinoma-associated sialyl-Lea epitope on distinct core proteins. J Biol Chem. 1991 Nov 15;266(32):21537–21547. [PubMed] [Google Scholar]
  3. Baeckström D., Karlsson N., Hansson G. C. Purification and characterization of sialyl-Le(a)-carrying mucins of human bile; evidence for the presence of MUC1 and MUC3 apoproteins. J Biol Chem. 1994 May 20;269(20):14430–14437. [PubMed] [Google Scholar]
  4. Boshell M., Lalani E. N., Pemberton L., Burchell J., Gendler S., Taylor-Papadimitriou J. The product of the human MUC1 gene when secreted by mouse cells transfected with the full-length cDNA lacks the cytoplasmic tail. Biochem Biophys Res Commun. 1992 May 29;185(1):1–8. doi: 10.1016/s0006-291x(05)80946-5. [DOI] [PubMed] [Google Scholar]
  5. Burchell J., Wang D., Taylor-Papadimitriou J. Detection of the tumour-associated antigens recognized by the monoclonal antibodies HMFG-1 and 2 in serum from patients with breast cancer. Int J Cancer. 1984 Dec 15;34(6):763–768. doi: 10.1002/ijc.2910340605. [DOI] [PubMed] [Google Scholar]
  6. Gendler S. J., Lancaster C. A., Taylor-Papadimitriou J., Duhig T., Peat N., Burchell J., Pemberton L., Lalani E. N., Wilson D. Molecular cloning and expression of human tumor-associated polymorphic epithelial mucin. J Biol Chem. 1990 Sep 5;265(25):15286–15293. [PubMed] [Google Scholar]
  7. Gendler S. J., Spicer A. P. Epithelial mucin genes. Annu Rev Physiol. 1995;57:607–634. doi: 10.1146/annurev.ph.57.030195.003135. [DOI] [PubMed] [Google Scholar]
  8. Gum J. R., Jr, Hicks J. W., Lagace R. E., Byrd J. C., Toribara N. W., Siddiki B., Fearney F. J., Lamport D. T., Kim Y. S. Molecular cloning of rat intestinal mucin. Lack of conservation between mammalian species. J Biol Chem. 1991 Nov 25;266(33):22733–22738. [PubMed] [Google Scholar]
  9. Jany B., Gallup M., Tsuda T., Basbaum C. Mucin gene expression in rat airways following infection and irritation. Biochem Biophys Res Commun. 1991 Nov 27;181(1):1–8. doi: 10.1016/S0006-291X(05)81373-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Karlsson N. G., Johansson M. E., Asker N., Karlsson H., Gendler S. J., Carlstedt I., Hansson G. C. Molecular characterization of the large heavily glycosylated domain glycopeptide from the rat small intestinal Muc2 mucin. Glycoconj J. 1996 Oct;13(5):823–831. doi: 10.1007/BF00702346. [DOI] [PubMed] [Google Scholar]
  11. Khatri I. A., Forstner G. G., Forstner J. F. Suggestive evidence for two different mucin genes in rat intestine. Biochem J. 1993 Sep 1;294(Pt 2):391–399. doi: 10.1042/bj2940391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Koller B. H., Kim H. S., Latour A. M., Brigman K., Boucher R. C., Jr, Scambler P., Wainwright B., Smithies O. Toward an animal model of cystic fibrosis: targeted interruption of exon 10 of the cystic fibrosis transmembrane regulator gene in embryonic stem cells. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10730–10734. doi: 10.1073/pnas.88.23.10730. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Ligtenberg M. J., Kruijshaar L., Buijs F., van Meijer M., Litvinov S. V., Hilkens J. Cell-associated episialin is a complex containing two proteins derived from a common precursor. J Biol Chem. 1992 Mar 25;267(9):6171–6177. [PubMed] [Google Scholar]
  14. Metzgar R. S., Rodriguez N., Finn O. J., Lan M. S., Daasch V. N., Fernsten P. D., Meyers W. C., Sindelar W. F., Sandler R. S., Seigler H. F. Detection of a pancreatic cancer-associated antigen (DU-PAN-2 antigen) in serum and ascites of patients with adenocarcinoma. Proc Natl Acad Sci U S A. 1984 Aug;81(16):5242–5246. doi: 10.1073/pnas.81.16.5242. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Patton S., Gendler S. J., Spicer A. P. The epithelial mucin, MUC1, of milk, mammary gland and other tissues. Biochim Biophys Acta. 1995 Dec 20;1241(3):407–423. doi: 10.1016/0304-4157(95)00014-3. [DOI] [PubMed] [Google Scholar]
  16. Pemberton L., Taylor-Papadimitriou J., Gendler S. J. Antibodies to the cytoplasmic domain of the MUC1 mucin show conservation throughout mammals. Biochem Biophys Res Commun. 1992 May 29;185(1):167–175. doi: 10.1016/s0006-291x(05)80971-4. [DOI] [PubMed] [Google Scholar]
  17. Pemberton L., Taylor-Papadimitriou J., Gendler S. J. Antibodies to the cytoplasmic domain of the MUC1 mucin show conservation throughout mammals. Biochem Biophys Res Commun. 1992 May 29;185(1):167–175. doi: 10.1016/s0006-291x(05)80971-4. [DOI] [PubMed] [Google Scholar]
  18. Rogers D. F. Airway goblet cells: responsive and adaptable front-line defenders. Eur Respir J. 1994 Sep;7(9):1690–1706. [PubMed] [Google Scholar]
  19. Samet J. M., Cheng P. W. The role of airway mucus in pulmonary toxicology. Environ Health Perspect. 1994 Jun;102 (Suppl 2):89–103. doi: 10.1289/ehp.9410289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Shekels L. L., Lyftogt C., Kieliszewski M., Filie J. D., Kozak C. A., Ho S. B. Mouse gastric mucin: cloning and chromosomal localization. Biochem J. 1995 Nov 1;311(Pt 3):775–785. doi: 10.1042/bj3110775. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Snouwaert J. N., Brigman K. K., Latour A. M., Malouf N. N., Boucher R. C., Smithies O., Koller B. H. An animal model for cystic fibrosis made by gene targeting. Science. 1992 Aug 21;257(5073):1083–1088. doi: 10.1126/science.257.5073.1083. [DOI] [PubMed] [Google Scholar]
  22. Spicer A. P., Parry G., Patton S., Gendler S. J. Molecular cloning and analysis of the mouse homologue of the tumor-associated mucin, MUC1, reveals conservation of potential O-glycosylation sites, transmembrane, and cytoplasmic domains and a loss of minisatellite-like polymorphism. J Biol Chem. 1991 Aug 15;266(23):15099–15109. [PubMed] [Google Scholar]
  23. Spicer A. P., Rowse G. J., Lidner T. K., Gendler S. J. Delayed mammary tumor progression in Muc-1 null mice. J Biol Chem. 1995 Dec 15;270(50):30093–30101. doi: 10.1074/jbc.270.50.30093. [DOI] [PubMed] [Google Scholar]
  24. Steiger D., Hotchkiss J., Bajaj L., Harkema J., Basbaum C. Concurrent increases in the storage and release of mucin-like molecules by rat airway epithelial cells in response to bacterial endotoxin. Am J Respir Cell Mol Biol. 1995 Mar;12(3):307–314. doi: 10.1165/ajrcmb.12.3.7873197. [DOI] [PubMed] [Google Scholar]
  25. Xu G., Huan L. J., Khatri I. A., Wang D., Bennick A., Fahim R. E., Forstner G. G., Forstner J. F. cDNA for the carboxyl-terminal region of a rat intestinal mucin-like peptide. J Biol Chem. 1992 Mar 15;267(8):5401–5407. [PubMed] [Google Scholar]
  26. Zhang K., Baeckström D., Brevinge H., Hansson G. C. Secreted MUC1 mucins lacking their cytoplasmic part and carrying sialyl-Lewis a and x epitopes from a tumor cell line and sera of colon carcinoma patients can inhibit HL-60 leukocyte adhesion to E-selectin-expressing endothelial cells. J Cell Biochem. 1996 Mar 15;60(4):538–549. doi: 10.1002/(SICI)1097-4644(19960315)60:4%3C538::AID-JCB10%3E3.0.CO;2-D. [DOI] [PubMed] [Google Scholar]

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