Abstract
1α,25-Dihydroxy vitamin D3[1α,25(OH)2D3] an active form of vitamin D, has roles in many biological phenomena such as calcium homeostasis and bone formation1–3, which are thought to be mediated by the 1α,25(OH)2D3 receptor (VDR), a member of the nuclear hormone receptor superfamily4–6. However, the molecular basis for the actions of 1α,25(OH)2D3 in bone formation, its role during development and VDR genetic polymorphisms for predicting bone mineral density7 are uncertain. To investigate the functional role of VDR, we generated mice deficient in VDR by gene targeting. We report here that in VDR null mutant mice, no defects in development and growth were observed before weaning, irrespective of reduced expression of vitamin D target genes. After weaning, however, mutants failed to thrive, with appearance of alopoecia, hypocalcaemia and infertility, and bone formation was severely impaired as a typical feature of vitamin D–dependent rickets type II (refs 8,9). Unlike humans with this disease, most of the null mutant mice died within 15 weeks after birth, and uterine hypoplasia with impaired folliculogenesis was found in female reproductive organs. These defects, such as alopoecia and uterine hypoplasia, were not observed in vitamin D–deficient animals. The findings establish a critical role for VDR in growth, bone formation and female reproduction in the post-weaning stage.
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References
Bouillon, R., Okamura, W.H. & Norman, A.W. Structure-function relationships in the vitamin D endocrine system. Endocr. Rev. 16, 200–257 (1995).
Studzinski, G.P., McLane, J.A. & Uskokovic, M.R. Signaling pathways for vitamin D-induced differentiation: implications for therapy of proliferative and neoplastic diseases. CRC Crit. Rev. Eukaryotic Gene Expression 3, 279–312 (1993).
Walters, M.R. Newly identified actions of the vitamin D endocrine system. Endocr. Rev. 13, 719–764 (1992).
Darwish, H. & DeLuca, H.F., D–regulated gene expression. CRC Crit. Rev. Eukaryotic Gene Expression 3, 89–116 (1993).
Kato, S. et al. Widely spaced, directly repeated PuGGTCA elements act as promiscuous enhancers for different classes of nuclear receptors. Mol. Cell. Biol. 15, 5858–5867 (1995).
Mangelsdorf, D.J. & Evans, R.M. The RXR heterodimers and orphan receptors. Cell 83, 841–850 (1995).
Morrison, N.A. et al. Prediction of bone density from vitamin D receptor alleles. Nature 367, 284–287 (1994).
Hawa, N.S. et al. Identification of a novel mutation in hereditary vitamin D resistant rickets causing exon skipping. Clin. Endocrinol. 45, 85–92 (1996).
Malloy, P.J. et al. The molecular basis of hereditary 1,25-dihydroxyvitamin D3 resistant rickets in seven related families. J. Clin. Invest. 86, 2071–2079 (1990).
Yagi, T. et al. A novel negative selection for homologous recombinants using diphtheria toxin A fragment gene. Anal. Biochem. 214, 77–86 (1993).
Ebihara, K. et al. Intron retention generates a novel isoform of the murine vitamin D receptor that acts in a dominant negative way on the vitamin D signaling pathway. Mol. Cell. Biol. 16, 3393–3400 (1996).
Harada, H., Miki, R., Masushige, S. & Kato, S. Gene expression of retinoic acid receptors, retinoid-X receptors, and cellular retinol-binding protein I in bone and its regulation by vitamin A. Endocrinology 136, 5329–5335 (1995).
Tabin, C.J. Retinoids, homeoboxes, and growth factors: toward molecular models for limb development. Cell 66, 199–217 (1991).
Kastner, P., Mark, M. & Chambon, P. Nonsteroid nuclear receptors: what are genetic studies telling us about their role in real life? CellS 3, 859–869 (1995).
Beresford, J.N., Gallagher, J.A. & Russell, R.G. 1,25-Dihydroxyvitamin D3 and human bone-derived cells in vitro: effects on alkaline phosphatase, type I collagen and proliferation. Endocrinology 119, 1776–1785 (1986).
Malloy, P.J., Weisman, Y. & Feldman, D. Hereditary 1 alpha,25-dihydroxyvitamin D-resistant rickets resulting from a mutation in the vitamin D receptor deoxyribonucleic acid-binding domain. J. Clin. Endocrinol. Metab. 78, 313–316 (1994).
Henry, H.L. & Norman, A.W. Vitamin D: metabolism and biological actions. Annu. Rev. Nutr. 4, 493–520 (1984).
Reeve, L., Tanaka, Y., & DeLuca, H.F Studies on the site of 1,25-dihydroxyvitamin D3 synthesis in vivo. J. Biol. Chem. 258, 3615–3617 (1983).
Kawashima, H., Torikai, S. & Kurokawa, K. Calcitonin selectively stimulates 25-hydroxyvitamin D3-1 α-hydroxylase in proximal straight tubule of rat kidney. Nature 291, 327–329 (1981).
Delvin, E.E. & Arabian, A. Kinetics and regulation of 25-hydroxycholecalciferol 1 α-hydroxylase from cells isolated from human term decidua. Eur. J. Biochem. 163, 659–662 (1987).
Noda, M. et al. Identification of a DNA sequence responsible for binding of the 1,25-dihydroxyvitamin D3 receptor and 1,25-dihydroxyvitamin D3 enhancement of mouse secreted phosphoprotein 1 (Spp1, osteopontin) gene expression. Proc. Natl. Acad. Sci. USA. 87, 9995–9999 (1990).
Kojima, R. et al. In vivo isomerization of retinoic acids: rapid isomer exchange and gene expression. J. Biol. Chem. 269, 32700–32707 (1994).
Abe, E. et al. Differentiation of mouse myeloid leukemia cells induced by 1 α,25-dihydroxyvitamin D3. Proc. Natl. Acad. Sci. USA. 78, 4990–4994 (1981).
Felig, P., Baxter, J.D., Frohman, L.A., eds. Endocrinology and Metabolism, 3rd ed (McGraw-Hill, New York, 1995).
Erlebacher, A., Filvaroff, E.H., Gitelman, S.E. & Derynck, R. Toward a molecular understanding of skeletal development. Cell 80, 371–378 (1995).
Martin, L., Finn, C.A. & Trinder, G. Hypertrophy and hyperplasia in the mouse uterus after oestrogen treatment: an autoradiographic study. J. Endocrinol. 56, 133–144 (1973).
Erickson, G.F. et al. An analysis of follicle development and ovum maturation. Semin. Reprod. Endocrinol. 4, 233–237 (1986).
Kastner, P. et al. Genetic analysis of RXR α developmental function: convergence of RXR and RAR signaling pathways in heart and eye morphogenesis. Cell 78, 987–1003 (1994).
Kato, S. et al. Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science 270, 1491–1494 (1995).
Lubahn, D.B. et al. Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. Proc. Natl. Acad. Sci. USA. 90, 11162–11166 (1993).
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Yoshizawa, T., Handa, Y., Uematsu, Y. et al. Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning. Nat Genet 16, 391–396 (1997). https://doi.org/10.1038/ng0897-391
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DOI: https://doi.org/10.1038/ng0897-391
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