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Diminished Milk Synthesis in Upstream Stimulatory Factor 2 Null Mice Is Associated With Decreased Circulating Oxytocin and Decreased Mammary Gland Expression of Eukaryotic Initiation Factors 4E and 4G

United States Department of Agriculture/Agricultural Research Service Children’s Nutrition Research Center (D.L.H., S.B., J.G., D.T., Y.K., S.G., P.M.H.), Department of Pediatrics and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030; Department of Pharmacology (J.S.-L.), The Pennsylvania State University, The Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033; Department of Obstetrics and Gynecology (M.S.S.), University of Texas Medical Branch, Galveston, Texas 77555; Harbor-UCLA Medical Center (A.F.P.), Torrance, California 90509; and Department of Molecular Genetics (M.Si., M.Sa.), The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Address all correspondence and requests for reprints to: Darryl Hadsell, United States Department of Agriculture/Agricultural Research Service Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030. E-mail: dhadsell{at}bcm.tmc.edu.

Previous studies have suggested that upstream stimulatory factors (USFs) regulate genes involved with cell cycle progression. Because of the relationship of USFs to an important oncogene in breast cancer, c-myc, we chose to determine the importance of USF to normal mammary gland development in the mouse. Expression of USF in the mammary gland throughout development demonstrated only modest changes. Mutation of the Usf2 gene was associated with reduced fertility in females, but had no effect on prepartum mammary gland development. However, lactation performance in Usf2^-/- females was only half of that observed in Usf2^+/+ females, and both lactose and nitrogen were decreased in milk from Usf2^-/- dams. This decrease was associated with diminished mammary tissue wet weight and luminal area by d 9 of lactation and with a decreased protein-DNA ratio. This decrease was associated with reduced abundance of the eukaryotic initiation factors eIF4E and eIF4G. Blood oxytocin concentrations on d 9 postpartum were also lower in Usf2^-/- mice than Usf2^+/+ mice. In contrast, the mutation had no effect on blood prolactin concentrations, mammary cell proliferation or apoptosis, mammary tissue oxytocin receptors, or milk protein gene expression. The mutation had only modest effects on maternal behavior. These data support the idea that USF is important to physiological processes necessary for the establishment and maintenance of normal lactation and suggest that USF-2 may impact lactation through both systemic and mammary cell-specific mechanisms.

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