title: ZnT4 (SLC30A4)-null ("lethal milk") mice have defects in mammary gland secretion and hallmarks of precocious involution during lactation.
abstract: During lactation, highly specialized secretory mammary epithelial cells (MECs) produce and secrete huge quantities of nutrients and nonnutritive factors into breast milk. The zinc (Zn) transporter ZnT4 (SLC30A4) transports Zn into the trans-Golgi apparatus for lactose synthesis, and across the apical cell membrane for efflux from MECs into milk. This is consistent with observations in "lethal milk" (lm/lm) mice, which have a truncation mutation in SLC30A4, and present with not only low milk Zn concentration, but also smaller mammary glands, decreased milk volume, and lactation failure by lactation day 2. However, the molecular underpinnings of these defects are not understood. Here, we used lactating C57BL/6J(lm/lm) (ZnT4-null) mice to explore the consequences of a ZnT4-null phenotype on mammary gland function during early lactation. Lactating C57BL/6J(lm/lm) mice had significantly fewer, smaller, and collapsed alveoli comprising swollen, lipid-filled MECs during early lactation. These defects were associated with decreased Akt expression and STAT5 activation, indicative of defects in MEC secretion. In addition, increased expression of ZnT2, TNF-α, and cleaved e-cadherin concomitant with increased activation of STAT3 implicated the loss of ZnT4 in precocious activation of involution. Collectively, our study indicates that the loss of ZnT4 has profound consequences on MEC secretion and may promote tissue remodeling in the mammary gland during early lactation.
authors.affiliation: Department of Nutritional Sciences, The Pennsylvania State University, University Park, Pennsylvania.
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: McCormick
authors.affiliation: Department of Cellular and Molecular Physiology, Penn State Hershey College of Medicine, Hershey, Pennsylvania;
authors.forename: Sooyeon
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Nutritional Sciences, The Pennsylvania State University, University Park, Pennsylvania.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Hennigar
authors.affiliation: Department of Cellular and Molecular Physiology, Penn State Hershey College of Medicine, Hershey, Pennsylvania; Department of Pharmacology, Penn State Hershey College of Medicine, Hershey, Pennsylvania; Department of Surgery, Penn State Hershey College of Medicine, Hershey, Pennsylvania; and Department of Nutritional Sciences, The Pennsylvania State University, University Park, Pennsylvania slk39@psu.edu.
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Kelleher
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism; D027682:Cation Transport Proteins / Q000172:deficiency* / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005838:Genotype; D007774:Lactation / Q000378:metabolism*; D008321:Mammary Glands, Animal / Q000378:metabolism* / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015820:Cadherins; D027682:Cation Transport Proteins; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C109053:Slc30a4 protein, mouse; C494087:Stat3 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D051057:Proto-Oncogene Proteins c-akt
keywords: SLC30A4; ZnT4; lactation; mammary gland; zinc