Nature Genetics
16, 391 - 396 (1997)
doi:10.1038/ng0897-391
Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaningTatsuya Yoshizawa1, Yuki Handa2, Yoshikatsu Uematsu2, Shu Takeda1, Keisuke Sekine1, Yuko Yoshihara2, Toru Kawakami2, Kouki Arioka2, Hiroshi Sato2, Yasushi Uchiyama3, Shoichi Masushige2, Akiyoshi Fukamizu4, Toshio Matsumoto5
& Shigeaki Kato1, 6
1Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113, Japan.
2Department of Agricultural Chemistry, Tokyo University of Agriculture, Sakuragaoka, Setagaya-ku, Tokyo 156, Japan.
3Fuji Gotenba Research Labs, Chugai Pharmaceutical Co., Gotenba-shi, Shizuoka 412, Japan.
4Institute of Applied Biochemistry, University of Tsukuba, Tsukuba 305, Japan.
5First Department of Internal Medecine, University of Tokushima, Tokushima 770, Japan.
6e-mail: uskato@hongo.ecc. u-tokyo.ac.jp 1 ,25-Dihydroxy vitamin D3[1,25(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 1,25(OH)2D3 receptor (VDR), a member of the nuclear hormone receptor superfamily4−6. However, the molecular basis for the actions of 1,25(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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