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Molecular Endocrinology 16 (7): 1524-1537
Copyright © 2002 by The Endocrine Society

Deletion of Deoxyribonucleic Acid Binding Domain of the Vitamin D Receptor Abrogates Genomic and Nongenomic Functions of Vitamin D

Reinhold G. Erben, Desi W. Soegiarto1, Karin Weber, Ute Zeitz, Michèle Lieberherr, Robert Gniadecki, Gabriele Möller, Jerzy Adamski and Rudi Balling2

Institute of Animal Physiology, Ludwig Maximilians University (R.G.E., K.W., U.Z.), 80539 Munich, Germany; Institute of Mammalian Genetics, GSF National Research Center for Environment and Health (D.W.S., R.B.), 85764 Neuherberg, Germany; National Center for Scientific Research, UPR 1524, National Institute of Agricultural Research (M.L.), 78 350 Jouy-en-Josas, France; Department of Dermatology D92, Bispebjerg Hospital (R.G.), 2400 Copenhagen NV, Denmark; and Institute of Experimental Genetics, GSF National Research Center for Environment and Health (G.M., J.A.), 85764 Neuherberg, Germany

Address all correspondence and requests for reprints to: Reinhold G. Erben, M.D., D.V.M., Institute of Animal Physiology, University of Munich, Veterinaerstrasse 13, D-80539 Munich, Germany. E-mail: r.erben{at}lrz.uni-muenchen.de.

The vitamin D hormone 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], the biologically active form of vitamin D, is essential for an intact mineral metabolism. Using gene targeting, we sought to generate vitamin D receptor (VDR) null mutant mice carrying the reporter gene lacZ driven by the endogenous VDR promoter. Here we show that our gene-targeted mutant mice express a VDR with an intact hormone binding domain, but lacking the first zinc finger necessary for DNA binding. Expression of the lacZ reporter gene was widely distributed during embryogenesis and postnatally. Strong lacZ expression was found in bones, cartilage, intestine, kidney, skin, brain, heart, and parathyroid glands. Homozygous mice are a phenocopy of mice totally lacking the VDR protein and showed growth retardation, rickets, secondary hyperparathyroidism, and alopecia. Feeding of a diet high in calcium, phosphorus, and lactose normalized blood calcium and serum PTH levels, but revealed a profound renal calcium leak in normocalcemic homozygous mutants. When mice were treated with pharmacological doses of vitamin D metabolites, responses in skin, bone, intestine, parathyroid glands, and kidney were absent in homozygous mice, indicating that the mutant receptor is nonfunctioning and that vitamin D signaling pathways other than those mediated through the classical nuclear receptor are of minor physiological importance. Furthermore, rapid, nongenomic responses to 1,25-(OH)2D3 in osteoblasts were abrogated in homozygous mice, supporting the conclusion that the classical VDR mediates the nongenomic actions of 1,25-(OH)2D3.




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