The vitamin D receptor functions as a transcription regulator in the absence of 1,25-dihydroxyvitamin D3.
The vitamin D receptor (VDR) is a critical mediator of the biological actions of 1,25-dihydroxyvitamin D3(1,25(OH)2D3). As a nuclear receptor, ligand activation of the VDR leads to the protein's binding to specific sites on the genome that results in the modulation of target gene expression. The VDR is also known to play a role in the hair cycle, an action that appears to be 1,25(OH)2D3-independent. Indeed, in the absence of the VDR as in hereditary 1,25-dihydroxyvitamin D resistant rickets (HVDRR) both skin defects and alopecia emerge. Recently, we generated a mouse model of HVDRR without alopecia wherein a mutant human VDR lacking 1,25(OH)2D3-binding activity was expressed in the absence of endogenous mouse VDR. While 1,25(OH)2D3failed to induce gene expression in these mice, resulting in an extensive skeletal phenotype, the receptor was capable of restoring normal hair cycling. We also noted a level of secondary hyperparathyroidism that was much higher than that seen in the VDR null mouse and was associated with an exaggerated bone phenotype as well. This suggested that the VDR might play a role in parathyroid hormone (PTH) regulation independent of 1,25(OH)2D3. To evaluate this hypothesis further, we contrasted PTH levels in the HVDRR mouse model with those seen in Cyp27b1 null mice where the VDR was present but the hormone was absent. The data revealed that PTH was indeed higher in Cyp27b1 null mice compared to VDR null mice. To evaluate the mechanism of action underlying such a hypothesis, we measured the expression levels of a number of VDR target genes in the duodena of wildtype mice and in transgenic mice expressing either normal or hormone-binding deficient mutant VDRs. We also compared expression levels of these genes between VDR null mice and Cyp27b1 null mice. In a subset of cases, the expression of VDR target genes was lower in mice containing the VDR as opposed to mice that did not. We suggest that the VDR may function as a selective suppressor/de-repressor of gene expression in the absence of 1,25(OH)2D3.
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, United States. Electronic address: smlee4@wisc.edu.
Seong Min
SM
Lee
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, United States.
J Wesley
JW
Pike
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000172:deficiency / Q000235:genetics*; D000818:Animals; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D002117:Calcitriol / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006197:Hair / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010281:Parathyroid Hormone / Q000097:blood / Q000235:genetics*; D018167:Receptors, Calcitriol / Q000172:deficiency / Q000235:genetics*; D063730:Rickets, Hypophosphatemic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D014158:Transcription, Genetic
D010281:Parathyroid Hormone; D018167:Receptors, Calcitriol; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol
1,25-Dihydroxyvitamin D(3)-independent action; Cyp27b1 null mice; Transcription repressor; Transcriptional de-repressor; VDR null mice