In vivo function of VDR in gene expression-VDR knock-out mice
In vivo function of VDR in gene expression-VDR knock-out mice
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DOI：
10.1016/s0960-0760(99)00042-4
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发表时间：
1999-04-01
影响因子：
4.1
通讯作者：
Yoshizawa, T
中科院分区：
文献类型：
--
作者：
Kato, S;Takeyama, K;Yoshizawa, T
维生素D通过核维生素D受体（VDR）介导的基因表达发挥多种生物学作用。VDR的反式激活功能通过结合维生素D的活性形式1 α，25-二羟基维生素D-3[1 α，25（OH）（2）D-3]而激活。25（OH）D-3的转化在肾脏中通过25（OH）D-3 1 α-羟化酶[25（OH）D 1 α-羟化酶]进行精细调节，保持1c（1，25（OH）2D 3的血清水平恒定。维生素D缺乏和VDR（II型遗传性佝偻病）等基因突变已知会导致佝偻病，如血清钙降低，脱发和骨形成受损。然而，维生素D-VDR系统在完整动物中维生素D作用的分子基础仍有待建立。此外，来自任何物种的1 α-羟化酶基因尚未被克隆，无论其生物学意义和与I型遗传性佝偻病的推定联系如何。我们产生了VDR缺陷小鼠（VDR KO小鼠）。VDR KO小鼠在断奶前生长正常，但断奶后出现II型佝偻病患者的异常。这些结果表明，维生素D-VDR系统在矿物质和骨代谢中的不可或缺性仅在断奶后的生活。使用一个新开发的克隆系统，我们克隆了编码一种新的P450酶，小鼠和人类1 α-羟化酶的cDNA。在VDR KO小鼠中的研究证明了配体VDR在1 α，25（OH）（2）D-3产生的负反馈调节中的功能。最后，通过对I型佝偻病患者的分析，我们发现1 α-羟化酶基因存在错义突变，从而得出该基因与I型佝偻病有关的结论。(C)1999爱思唯尔科技有限公司。保留所有权利。
Vitamin D exerts many biological actions through nuclear vitamin D receptor (VDR)-mediated gene expression. The transactivation function of VDR is activated by binding 1 alpha,25-dihydroxyvitamin D-3[1 alpha,25(OH)(2)D-3], an active form of vitamin D. Conversion from 25(OH)D-3 is finely regulated in kidney by 25(OH)D-3 1 alpha-hydroxylase[25(OH)D 1 alpha-hydroxylase], keeping serum levels of lc(,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 1 alpha-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 1 alpha-hydroxylase. The study in VDR KO mice demonstrated the function of liganded VDR in the negative feed-back regulation of 1 alpha,25(OH)(2)D-3 production. Finally, from the analysis of type I rickets patients, we found missense genetic mutations in 1 alpha-hydroxylase, leading to the conclusion that this gene is responsible for the type I rickets. (C) 1999 Elsevier Science Ltd. All rights reserved.