In vivo function of VDR in gene expression-VDR knock-out mice.
Vitamin D exerts many biological actions through nuclear vitamin D receptor (VDR)-mediated gene expression. The transactivation function of VDR is activated by binding 1alpha,25-dihydroxyvitamin D3[1alpha,25(OH)2D3], an active form of vitamin D. Conversion from 25(OH)D3 is finely regulated in kidney by 25(OH)D3 1alpha-hydroxylase[25(OH)D 1alpha-hydroxylase], keeping serum levels of 1alpha,25(OH)2D3 constant. Deficiency of vitamin D and mutations in the genes like VDR (type II genetic rickets) are known to cause rickets like lowered serum calcium, alopecia and impaired bone formation. However, the molecular basis of vitamin D VDR system in the vitamin D action in intact animals remained to be established. In addition, the 1alpha-hydroxylase gene from any species had not yet been cloned, irrespective of its biological significance and putative link to the type I genetic rickets. We generated VDR-deficient mice (VDR KO mice). VDR KO mice grew up normally until weaning, but after weaning they developed abnormality like the type II rickets patients. These results demonstrated indispensability of vitamin D-VDR system in mineral and bone metabolism only in post-weaning life. Using a newly developed cloning system, we cloned the cDNA encoding a novel P450 enzyme, mouse and human 1alpha-hydroxylase. The study in VDR KO mice demonstrated the function of liganded VDR in the negative feed-back regulation of 1alpha,25(OH)2D3 production. Finally, from the analysis of type I rickets patients, we found missense genetic mutations in 1alpha-hydroxylase, leading to the conclusion that this gene is responsible for the type I rickets.
Institute of Molecular and Cellular Biosciences, The University of Tokyo, Japan. uskato@hongo.ecc.u-tokyo.ac.jp
S
S
Kato
K
K
Takeyama
S
S
Kitanaka
A
A
Murayama
K
K
Sekine
T
T
Yoshizawa
D000818:Animals; D001846:Bone Development; D003001:Cloning, Molecular; D005786:Gene Expression Regulation / Q000187:drug effects; D018390:Gene Targeting; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D018167:Receptors, Calcitriol / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D012279:Rickets / Q000235:genetics; D013250:Steroid Hydroxylases / Q000235:genetics; D014807:Vitamin D / Q000494:pharmacology
D018167:Receptors, Calcitriol; D014807:Vitamin D; D013250:Steroid Hydroxylases