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The Role of ZnT2 in the Mammary Gland during Lactation
Author(s) -
Lee Sooyeon,
Soybel David,
Kelleher Shan
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.121.6
Subject(s) - lactation , mammary gland , endoplasmic reticulum , lipid droplet , casein , medicine , endocrinology , biology , breast milk , lactose , chemistry , microbiology and biotechnology , biochemistry , genetics , pregnancy , cancer , breast cancer
Successful lactation requires optimal regulation of mammary gland (MG) differentiation, milk secretion and milk composition. We and others have reported four “loss‐of‐function” mutations in the zinc (Zn) transporter ZnT2 that reduce milk Zn levels by ~75% causing transient neonatal Zn deficiency. However, ZnT2 plays multifactorial roles in MG biology and effects of ZnT2 dysfunction have not been explored. We used lactating ZnT2‐null (ZnT2ko) mice to identify consequences of loss of ZnT2 function during lactation. Similar to women with mutations in ZnT2, lactating ZnT2ko mice had significantly lower milk Zn levels. In addition, we found that the major milk components, b‐casein, lactose and fat were significantly reduced by ~40% in ZnT2ko mice. Lactating ZnT2ko mice had substantial defects in MG architecture and function including fewer, condensed and disorganized alveoli and reduced Stat5 activation. Morphological analysis revealed lipid droplet accumulation in engorged mammary epithelial cells (MECs) lining the alveoli, indicating secretory inactivation. Electron microscopy illustrated that MECs were unpolarized and severely disorganized with swollen mitochondria and fragmented endoplasmic reticulum and lipid accumulation. Consequently, milk volume was significantly reduced and less than 50% of ZnT2ko dams had surviving litters. Taken together, our results establish that ZnT2 is a critical regulator of MG function to ensure optimal milk quality and function during lactation. Finally, our study suggests that women with mutations in ZnT2 may be at risk for sub‐optimal milk composition and insufficient lactation.