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Submitted on December 4, 2003
Accepted on May 25, 2004
Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556
* To whom correspondence should be addressed. E-mail: jwelsh3{at}nd.edu.
The vitamin D receptor (VDR) is present in mammary gland, and VDR ablation is associated with accelerated glandular development during puberty. VDR is a nuclear receptor whose ligand, 1,25-dihydroxyvitamin D (1,25-(OH)2D) is generated after metabolic activation of vitamin D by specific vitamin D hydroxylases. In these studies, we demonstrate that both the VDR and the vitamin D 1-
hydroxylase (CYP27B1) which produces 1,25-(OH)2D are present in mammary gland and dynamically regulated during pregnancy, lactation and involution. Furthermore, we show that mice lacking VDR exhibit accelerated lobuloalveolar development and premature casein expression during pregnancy and delayed post-lactational involution compared with mice with functional VDR. The delay in mammary gland regression after weaning of VDR KO mice is associated with impaired apoptosis as demonstrated by reductions in TUNEL staining, caspase-3 activation and Bax induction. Under the conditions used in this study, VDR ablation was not associated with hypocalcemia, suggesting that altered mammary gland development in the absence of the VDR is not related to disturbances in calcium homeostasis. Furthermore, in the setting of normocalcemia, VDR ablation does not affect milk protein or calcium content. These studies suggest that the VDR contributes to mammary cell turnover during the reproductive cycle, and its effects may be mediated via both endocrine and autocrine signaling pathways. Unlike many mammary regulatory factors which exert transient, stage specific effects, VDR signaling impacts on mammary gland biology during all phases of the reproductive cycle.
-hydroxylase •
Vitamin D3 Receptor Knockout
NURSA Molecule Pages Link:
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