Tight Junction Regulation in the Mammary Gland

  • Duy-Ai D. Nguyen
  • Margaret C. Neville


Tight junctions form a narrow, continuous sealthat surrounds each endothelial and epithelial cell atthe apical border, and act to regulate the movement ofmaterial through the paracellular pathway. In the mammary gland, the tight junctions of thealveolar epithelial cells are impermeable duringlactation, and thus allow milk to be stored betweennursing periods without leakage of milk components from the lumen. Nonetheless mammary epithelial tightjunctions are dynamic and can be regulated by a numberof stimuli. Tight junctions of the mammary gland fromthe pregnant animal are leaky, undergoing closure around parturition to become the impermeabletight junctions of the lactating animal. Milk stasis,high doses of oxytocin, and mastitis have been shown toincrease tight junction permeability. In general changes in tight junction permeability in themammary gland appear to be the results of a state changeand not assembly and disassembly of tight junctions.Both local factors, such as intramammary pressure and TGF-beta, and systemic factors, such asprolactin, progesterone, and glucocorticoids, appear toplay a role in the regulation of mammary tightjunctions. Finally, the tight junction state appears to be closely linked to milk secretion. Anincrease in tight junction permeability is accompaniedby decrease in the milk secretion rate, and conversely,a decrease in tight junction permeability is accompanied by an increase in the milk secretionrate.



Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    B. R. Stevenson, J. M. Anderson, and S. Bullivant (1988). The epithelial tight junction: Structure, function and preliminary biochemical characterization. Mol. Cell Biochem. 83: 129-145.Google Scholar
  2. 2.
    D. B. van and J. H. Luft (1979). Effects of glutaraldehyde fixation on the structure of tight junctions: A quantitative freeze-fracture analysis. J. Ultrastr. Res. 68: 160-172.Google Scholar
  3. 3.
    d. S. Pinto and B. Kachar (1982). On tight-junction structure. Cell 28: 441-450.Google Scholar
  4. 4.
    L. Turin, P. Behe, I. Plonsky, and A. Dunina-Barkovskaya (1991). Hydrophobic ion transfer between membranes of adjacent hepatocytes: A possible probe of tight junction structure. Proc. Natl. Acad. Sci U.S.A. 88: 9365-9369.Google Scholar
  5. 5.
    H. W. Meyer (1984). [Current findings for the interpretation of “tight junctions” as lipid structures]. Acta Histochem.-Suppl. 30: 291-300.Google Scholar
  6. 6.
    K. Grebenkamper and H. J. Galla (1994). Translational diffusion measurements of a fluorescent phospholipid between MDCK-I cells support the lipid model of the tight junctions. Chem. Phys. Lipids 71: 133-143.Google Scholar
  7. 7.
    R. G. Miller and W. H. Baldridge (1985). The tight junction as a barrier to cholesterol in canine epithelial cells. J. Ultrastr. Res. 90: 275-285.Google Scholar
  8. 8.
    G. van Meer, B. Gumbiner, and K. Simons (1986). The tight junction does not allow lipid molecules to diffuse from one epithelial cell to the next. Nature 322: 639-641.Google Scholar
  9. 9.
    M. Furuse, T. Hirase, M. Itoh, A. Nagafuchi, S. Yonemura, and S. Tsukita (1993). Occludin: A novel integral membrane protein localizing at tight junctions [see comments]. J. Cell Biol. 123: 1777-1788.Google Scholar
  10. 10.
    K. Fujimoto (1995). Freeze-fracture replica electron microscopy combined with SDS digestion for cytochemical labeling of integral membrane proteins. Application to the immunogold labeling of intercellular junctional complexes. J. Cell Sci. 108: 3443-3449.Google Scholar
  11. 11.
    J. M. Anderson and I. C. Van (1995). Tight junctions and the molecular basis for regulation of paracellular permeability. Am. J. Physiol. 269: G467-G475.Google Scholar
  12. 12.
    M. Furuse, M. Itoh, T. Hirase, A. Nagafuchi, S. Yonemura, and S. Tsukita (1994). Direct association of occludin with ZO-1 and its possible involvement in the localization of occludin at tight junctions. J. Cell Biol. 127: 1617-1626.Google Scholar
  13. 13.
    V. Wong and B. M. Gumbiner (1997). A synthetic peptide corresponding to the extracellular domain of occludin perturbs the tight junction permeability barrier. J. Cell Biol. 136: 399-409.Google Scholar
  14. 14.
    B. H. Keon, S. Schafer, C. Kuhn, C. Grund, and W. W. Franke (1996). Symplekin, a novel type of tight junction plaque protein. J. Cell Biol. 134: 1003-1018.Google Scholar
  15. 15.
    J. Gottardi, M. Arpin, A. S. Fanning, and D. Louvard (1996). The junction-associated protein, zonula occludens-1, localizes to the nucleus before the maturation and during the remodeling of cell-cell contacts. Proc. Natl. Acad. Sci U.S.A. 93: 10779-10784.Google Scholar
  16. 16.
    T. Yamamoto, N. Harada, K. Kano, S. Taya, E. Canaani, Y. Matsuura, A. Mizoguchi, C. Ide, and K. Kaibuchi (1997). The Ras target AF-6 interacts with ZO-1 and serves as a peripheral component of tight junctions in epithelial cells. J. Cell Biol. 139: 785-795.Google Scholar
  17. 17.
    J. L. Linzell and M. Peaker (1973). Changes in mammary gland permeability at the onset of lactation in the goat: An effect on tight junctions? J. Physiol. (Lond.) 230: 13P-14P.Google Scholar
  18. 18.
    M. C. Neville (1995). Determinants of milk volume and composition. A. Lactogenesis in women: A cascade of events revealed by milk composition. In R. G. Jensen (eds.), Handbook of Milk Composition San Diego, Academic Press, pp. 87-98.Google Scholar
  19. 19.
    J. L. Linzell and M. Peaker (1974). Changes in colostrum composition and in the permeability of the mammary epithelium at about the time of parturition in the goat. J. Physiol.(Lond.) 243: 129-151.Google Scholar
  20. 20.
    J. L. Linzell and M. Peaker (1971). The permeability of mammary ducts. J. Physiol. (Lond.) 216: 701-716.Google Scholar
  21. 21.
    M. Peaker (1977). Mechanism of milk secretion: milk composition in relation to potential difference across the mammary epithelium. J. Physiol. (Lond.) 270: 489-505.Google Scholar
  22. 22.
    S. E. Berga (1984). Electrical potentials and cell-to-cell dye movement in mouse mammary gland during lactation. Am. J. Physiol. 247: C20-C25.Google Scholar
  23. 23.
    D. R. Pitelka, S. T. Hamamoto, J. G. Duafala, and M. K. Nemanic (1973). Cell contacts in the mouse mammary gland. I. Normal gland in postnatal development and the secretory cycle. J. Cell Biol. 56: 797-818.Google Scholar
  24. 24.
    O. Claesson, A. Hanson, N. Gustafsson, and E. Brannang (1959). Studies on monozygous cattle twins. XVII. Once-a-day milking compared with twice-a-day milking. Acta Agric. Scand. 9: 38-58.Google Scholar
  25. 25.
    C. W. Holmes, G. F. Wilson, D. D. S. MacKenzie, and J. Purchas (1992). The effects of milking once daily throughout lactation on the performance of dairy cows grazing on pasture. Proc. N. Z. Soc. Anim. Prod. 52: 12-16.Google Scholar
  26. 26.
    C. J. Wilde and C. H. Knight (1990). Milk yield and mammary function in goats during and after once-daily milking. J. Dairy. Res. 57: 441-447.Google Scholar
  27. 27.
    M. Morag (1968). The effect of varying the daily milking frequency on the milk yield of the ewe and evidence on the nature of the inhibition of milk ejection by half-udder milking. Ann. Zootech. 17: 351-369.Google Scholar
  28. 28.
    K. Stelwagen, S. R. Davis, V. C. Farr, C. G. Prosser, and R. A. Sherlock (1994). Mammary epithelial cell tight junction integrity and mammary blood flow during an extended milking interval in goats. J. Dairy Sci. 77: 426-432.Google Scholar
  29. 29.
    K. Stelwagen, V. C. Farr, H. A. McFadden, C. G. Prosser, and S. R. Davis (1997). Time course of milk accumulation-induced opening of mammary tight junctions, and blood clearance of milk components. Am. J. Physiol. 273: R379-R386.Google Scholar
  30. 30.
    K. Stelwagen, V. C. Farr, S. R. Davis, and C. G. Prosser (1995). EGTA-induced disruption of epithelial cell tight junctions in the lactating caprine mammary gland. Am. J. Physiol. 269: R848-R855.Google Scholar
  31. 31.
    M. C. Neville and M. Peaker (1981). Ionized calcium in milk and the integrity of the mammary epithelium in the goat. J. Physiol. (Lond.) 313: 561-570.Google Scholar
  32. 32.
    K. Stelwagen and C. H. Knight (1997). Effect of unilateral once or twice daily milking of cows on milk yield and udder characteristics in early and late lactation [in process citation]. J. Dairy Res. 64: 487-494.Google Scholar
  33. 33.
    K. Stelwagen and S. J. Lacy-Hulbert (1996). Effect of milking frequency on milk somatic cell count characteristics and mammary secretory cell damage in cows. Am. J. Vet. Res. 57: 902-905.Google Scholar
  34. 34.
    C. J. Wilde, C. V. Addey, L. M. Boddy, and M. Peaker (1995). Autocrine regulation of milk secretion by a protein in milk. Biochem. J. 305: 51-58.Google Scholar
  35. 35.
    A. W. Sudlow and R. D. Burgoyne (1997). A hypo-osmotically induced increase in intracellular Ca2+ in lactating mouse mammary epithelial cells involving Ca2+ influx. Pflugers Arch. 433: 609-616.Google Scholar
  36. 36.
    I. D. Millar, M. C. Barber, M. A. Lomax, M. T. Travers, and D. B. Shennan (1997). Mammary protein synthesis is acutely regulated by the cellular hydration state. Biochem. Biophys. Res. Commun. 230: 351-355.Google Scholar
  37. 37.
    I. R. Fleet and M. Peaker (1978). Mammary function and its control at the cessation of lactation in the goat. J. Physiol. (Lond.) 279: 491-507.Google Scholar
  38. 38.
    A. Hanwell and J. L. Linzell (1973). The effects of engorgement with milk and of suckling on mammary blood flow in the rat. J. Physiol. (Lond.) 233: 111-125.Google Scholar
  39. 39.
    J. L. Linzell and M. Peaker (1972). Day-to-day variations in milk composition in the goat and cow as a guide to the detection of subclinical mastitis. Br. Vet. J. 128: 284-295.Google Scholar
  40. 40.
    D. B. Symons and L. J. Wright (1974). Changes in bovine mammary gland permeability after intramammary exotoxin infusion. J. Comp. Pathol. 84: 9-17.Google Scholar
  41. 41.
    A. J. Frost, B. E. Brooker, and A. W. Hill (1984). The effect of Escherichia coli endotoxin and culture filtrate on the lactating bovine mammary gland. Aust. Vet. J. 61: 77-82.Google Scholar
  42. 42.
    L. Leach and J. A. Firth (1997). Structure and permeability of human placental microvasculature. Microsc. Res. Tech. 38: 137-144.Google Scholar
  43. 43.
    J. L. Madara and J. Stafford (1989). Interferon-gamma directly affects barrier function of cultured intestinal epithelial mono-layers. J. Clin. Invest. 83: 724-727.Google Scholar
  44. 44.
    T. Mattila, J. Syvajarvi, N. E. Jensen, and M. Sandholm (1986). N-acetyl-beta-D-glucosaminid ase and antitrypsin in subclinically infected quarter-milk samples: Effect of bacteria and hemolysins, lactation stage, and lactation number. Am. J. Vet. Res. 47: 139-142.Google Scholar
  45. 45.
    L. H. Thomas, W. Haider, A. W. Hill, and R. S. Cook (1994). Pathologic findings of experimentally induced Streptococcus uberis infection in the mammary gland of cows. Am. J. Vet. Res. 55: 1723-1728.Google Scholar
  46. 46.
    J. L. Linzell, M. Peaker, and J. C. Taylor (1975). The effects of prolactin and oxytocin on milk secretion and on the permeability of the mammary epithelium in the rabbit. J. Physiol. (Lond.) 253: 547-563.Google Scholar
  47. 47.
    J. C. Allen (1990). Milk synthesis and secretion rates in cows with milk composition changed by oxytocin. J.Dairy Sci. 73: 975-984.Google Scholar
  48. 48.
    I. R. Falconer, I. A. Forsyth, B. M. Wilson, and R. Dils (1978). Inhibition by low concentrations of ouabain of prolactin-induced lactogenesis in rabbit mammary-gland explants. Biochem. J. 172: 509-516.Google Scholar
  49. 49.
    M. L. Ledbetter and M. Lubin (1977). Control of protein synthesis in human fibroblasts by intracellular potassium. Exp. Cell Res. 105: 223-236.Google Scholar
  50. 50.
    I. A. Forsyth (1983). The Endocrinology of Lactation. In T. B. Mepham (eds.), Biochemistry of Lactation, Amsterdam, Elsevier Science Publishers, pp. 309-350.Google Scholar
  51. 51.
    G. E. Thompson (1996). Cortisol and regulation of tight junctions in the mammary gland of the late-pregnant goat. J. Dairy Res. 63: 305-308.Google Scholar
  52. 52.
    K. S. Zettl, M. D. Sjaastad, P. M. Riskin, G. Parry, T. E. Machen, and G. L. Firestone (1992). Glucocorticoid-induced formation of tight junctions in mouse mammary epithelial cells in vitro. Proc. Natl. Acad. Sci. U.S.A. 89: 9069-9073.Google Scholar
  53. 53.
    K. L. Singer, B. R. Stevenson, P. L. Woo, and G. L. Firestone (1994). Relationship of serine/threonine phosphorylation/dephosphorylation signaling to glucocorticoid regulation of tight junction permeability and ZO-1 distribution in nontransformed mammary epithelial cells. J. Biol. Chem. 269: 16108-16115.Google Scholar
  54. 54.
    P. L. Woo, H. H. Cha, K. L. Singer, and G. L. Firestone (1996). Antagonistic regulation of tight junction dynamics by glucocorticoids and transforming growth factor-beta in mouse mammary epithelial cells. J. Biol. Chem. 271: 404-412.Google Scholar
  55. 55.
    S. D. Robinson, G. B. Silberstein, A. B. Roberts, K. C. Flanders, and C. W. Daniel (1991). Regulated expression and growth inhibitory effects of transforming growth factor-beta isoforms in mouse mammary gland development. Development 113: 867-878.Google Scholar
  56. 56.
    R. Strange, F. Li, R. R. Friis, E. Reichmann, B. Haenni, and P. H. Burri (1991). Mammary epithelial differentiation in vitro: Minimum requirements for a functional response to hormonal stimulation. Cell Growth Differ. 2: 549-559.Google Scholar
  57. 57.
    S. D. Robinson, A. B. Roberts, and C. W. Daniel (1993). TGF beta suppresses casein synthesis in mouse mammary explants and may play a role in controlling milk levels during pregnancy. J. Cell Biol. 120: 245-251.Google Scholar
  58. 58.
    A. T. Cowie, P. E. Hartmann, and A. Turvey (1969). The maintenance of lactation in the rabbit after hypophysectomy. J. Endocrinol. 43: 651-662.Google Scholar
  59. 59.
    D. J. Flint and M. Gardner (1994). Evidence that growth hormone stimulates milk synthesis by direct action on the mammary gland and that prolactin exerts effects on milk secretion by maintenance of mammary deoxyribonucleic acid content and tight junction status. Endocrinology 135: 1119-1124.Google Scholar
  60. 60.
    L. G. Sheffield and L. C. Kotolski (1992). Prolactin inhibits programmed cell death during mammary gland involution. FASEB J. 6: A1184.Google Scholar
  61. 61.
    N. J. Kuhn (1969). Progesterone withdrawal as the lactogenic trigger in the rat. J. Endocrinol. 44: 39-54.Google Scholar
  62. 62.
    S. Nishikawa, R. C. Moore, N. Nonomura, and T. Oka (1994). Progesterone and EGF inhibit mouse mammary gland prolactin receptor and beta-casein gene expression. Am. J. Physiol. 267: C1467-C1472.Google Scholar
  63. 63.
    W. F. Maule and M. Peaker (1980). Local production of prostaglandins in relation to mammary function at the onset of lactation in the goat. J. Physiol. (Lond.) 309: 65-79.Google Scholar
  64. 64.
    P. B. Pickett, D. R. Pitelka, S. T. Hamamoto, and D. S. Misfeldt (1975). Occluding junctions and cell behavior in primary cultures of normal and neoplastic mammary gland cells. J. Cell Biol. 66: 316-332.Google Scholar

Copyright information

© Plenum Publishing Corporation 1998

Authors and Affiliations

  • Duy-Ai D. Nguyen
  • Margaret C. Neville

There are no affiliations available

Personalised recommendations