SUMMARY

A. Regulation of tight junction closure in the mammary gland during transition from pregnancy to lactation. The mammary gland undergoes a rapid programmed differentiation response set in motion by the fall in progesterone after parturition. Although this is an important switching point for the onset of milk secretion and appears to be under the control of both systemic and local factors, the regulation of lactogenesis has received remarkably little attention in the last 20 years!! One of the early changes is closure of the tight junctions between mammary alveolar cells. We are using advanced molecular and cell biological techniques to identify the changes in gene expression and protein phosphorylation that underlie this transition.

B. Transcytosis of extra-alveolar proteins. Milk contains many substances that are transferred unaltered from the plasma and interstitial space of the mammary gland. We have recently discovered a very active transcytotic pathway in the mammary epithelium of the lactating mouse. Although it has long been known that this pathway existed for immunoglobulins and some hormones like prolactin, we have shown that it transfers any material put into the interstitial fluid very rapidly into milk. Plasma components that are transferred in this way include albumin and LDL. We are currently studying the cell biology of this pathway in relation to the secretory pathway and the pathways for receptor-mediated transcytosis of IgA and prolactin. We postulate that this pathway may be important in the transfer of vitamins, minerals and other minor, but important, components of milk.

C. Regulation and role of lactoferrin in milk. The iron-binding protein lactoferrin is one of four major proteins in human milk. Because concentrations of the protein in bovine milk are very low, it is not present in infant formula. We are currently using transgenic mice that overexpress human lactoferrin in their milk to determine the role of this protein in iron transfer to the infant, in neonatal intestinal development and in protection against enteric infection. The same transgenic mice will be used to examine the function of lactoferrin in the mammary gland as well as aspects of the regulation of its secretion which differs from that of other milk proteins.

Projects within all these areas of investigation are available to trainees.

• Zhang, P. Sawicki,V., Lewis, A., Hanson, L., Monks, J., Neville, M.C.  (1999)  The effect of low iron diets on iron secretion into mouse milk.   J.Physiol.  233: 479-491.
• Monks, J.  P.U. Huey, Hanson, L., Eckel, R.H., Neville, M.C. and Gavigan, S. (2000) Cholesterol-depleted, low density lipoprotein-sized particles are present in the milk of lactating mice.  J. Lipid Research. In revision.
• McManaman, J.L., Neville, M.C. and Wright R.M. (1999)  Mouse mammary gland xanthine oxidoreductase: Purification, characterization and regulation.   Arch. Biochem. Biophys. 371(2):308-16.
• McManaman, J.L., Hanson, L., Wright, R.M. and Neville, M.C. (2000)  Lactogenic hormones regulate xanthine oxidoreductase and  -casein levels in mammary epithelial cells by distinct mechanisms. Arch. Biochem. Biophys. 373(2):318-27.
• Nguyen D-AD, Beeman NG, Lewis MT, Schaack J, Neville MC. (2000) Intraductal injection into the mouse mammary gland. In: Ip MM, Asch B, eds. Methods in Mammary Gland Biology and Breast Cancer Research. New York: Kluwer Academic, New York. In press

 Nguyen D-AD, Neville MC. (2000) Hormonal regulation of tight junction closure in the pregnant mouse. 2000; Submitted.

• Nguyen, D.D. and Neville, M.C. (1998)  Tight junction regulation in the mammary gland.  J. Mammary Gland Biol. Neoplasia.  3:233-246.
• Neville, M.C., Medina, C. Monks, J. and Hovey, R.C. (1998)  Editorial Commentary:  The mammary fat pad.  J. Mammary Gland Biol. Neoplasia.  3:109-116.
• Neville, M.C.  (1999)  Physiology of Lactation.  Clinics in Perinatology,  June.
• Neville, M.C.   (1999)  Adaptation of maternal lipid flux to pregnancy:  Research needs.  Eur.J.Clin.Nutrition.  53:S120-S123.
• Semba RD, Neville MC.   (1999)  Breast-feeding, mastitis, and HIV transmission: nutritional implications.    Nutr Rev. 57:146-53.
• Monks, J.A. and Neville, M.C.   (2001) Transcytosis of proteins across the mammary epithelium into milk.  Journal of Women’s Health.  In Press 
• Umemura, S., Morton, J. and Neville, M.C.  (2001) Lactogenesis: the transition from pregnancy to lactation.  Ped.Clin. N.A.  In Press.

• Nguyen,D.-A. and M.C. Neville (1995) Tight junction closure during lactogenesis in the mouse mammary gland. American Society for Cell Biology, Washington, D.C. 
• M.C. Neville, V.S. Toddywalla, F.W. Kari, J. Monks, S.J.P. Gavigan (1996) Drug and protein transfer into milk: A reevaluation. Experimental Biology '96. 
• D.-A.Nguyen and M.C. Neville. Tight junction regulation in the mouse mammary gland. International Congress of Physiology, St. Petersburg, June, 1997. 
• D.-A.Nguyen and M. C. Neville, Tight junction regulation in the mouse mammary gland. Gordon Conference on Mammary Gland Biology, June, 1997.
• J.Monks and M.C. Neville, A promiscuous transcytotic pathway in the lactating mouse mammary gland. Gordon Conference on Mammary Gland Biology, June, 1997. 

  ---