RGD Reference Report - Generation of novel genetically modified rats to reveal the molecular mechanisms of vitamin D actions. - Rat Genome Database

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Generation of novel genetically modified rats to reveal the molecular mechanisms of vitamin D actions.

Authors: Nishikawa, Miyu  Yasuda, Kaori  Takamatsu, Masashi  Abe, Keisuke  Okamoto, Kairi  Horibe, Kyohei  Mano, Hiroki  Nakagawa, Kimie  Tsugawa, Naoko  Hirota, Yoshihisa  Horie, Tetsuhiro  Hinoi, Eiichi  Okano, Toshio  Ikushiro, Shinichi  Sakaki, Toshiyuki 
Citation: Nishikawa M, etal., Sci Rep. 2020 Mar 30;10(1):5677. doi: 10.1038/s41598-020-62048-1.
RGD ID: 32716373
Pubmed: PMID:32231239   (View Abstract at PubMed)
PMCID: PMC7105495   (View Article at PubMed Central)
DOI: DOI:10.1038/s41598-020-62048-1   (Journal Full-text)

Recent studies have suggested that vitamin D activities involve vitamin D receptor (VDR)-dependent and VDR-independent effects of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) and 25-hydroxyvitamin D3 (25(OH)D3) and ligand-independent effects of the VDR. Here, we describe a novel in vivo system using genetically modified rats deficient in the Cyp27b1 or Vdr genes. Type II rickets model rats with a mutant Vdr (R270L), which recognizes 1,25(OH)2D3 with an affinity equivalent to that for 25(OH)D3, were also generated. Although Cyp27b1-knockout (KO), Vdr-KO, and Vdr (R270L) rats each showed rickets symptoms, including abnormal bone formation, they were significantly different from each other. Administration of 25(OH)D3 reversed rickets symptoms in Cyp27b1-KO and Vdr (R270L) rats. Interestingly, 1,25(OH)2D3 was synthesized in Cyp27b1-KO rats, probably by Cyp27a1. In contrast, the effects of 25(OH)D3 on Vdr (R270L) rats strongly suggested a direct action of 25(OH)D3 via VDR-genomic pathways. These results convincingly suggest the usefulness of our in vivo system.



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Biological Process

  

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Object Symbol
Species
Term
Qualifier
Evidence
With
Notes
Source
Original Reference(s)
Cyp27b1Ratabnormal cartilage morphology  IMP  RGD 
Cyp27b1em1ThkaRatabnormal cartilage morphology  IMP  RGD 
VdrRatabnormal cartilage morphology  IMP  RGD 
Vdrem1ThkaRatabnormal cartilage morphology  IMP  RGD 
Vdrem2ThkaRatabnormal cartilage morphology  IMP  RGD 
W-Cyp27b1em1ThkaRatabnormal cartilage morphology  IMP  RGD 
W-Vdrem1ThkaRatabnormal cartilage morphology  IMP  RGD 
W-Vdrem2ThkaRatabnormal cartilage morphology  IMP  RGD 
Cyp27b1Ratabnormal femur morphology treatmentIMPvitamin D3compared to Jcl:Wi and untreatedRGD 
Cyp27b1em1ThkaRatabnormal femur morphology treatmentIMPvitamin D3compared to Jcl:Wi and untreatedRGD 
VdrRatabnormal femur morphology  IMP  RGD 
Vdrem1ThkaRatabnormal femur morphology  IMP  RGD 
W-Cyp27b1em1ThkaRatabnormal femur morphology treatmentIMPvitamin D3compared to Jcl:Wi and untreatedRGD 
W-Vdrem1ThkaRatabnormal femur morphology  IMP  RGD 
VdrRatabnormal skin appearance  IMP  RGD 
Vdrem2ThkaRatabnormal skin appearance  IMP  RGD 
W-Vdrem2ThkaRatabnormal skin appearance  IMP  RGD 
Cyp27b1Ratabnormal survival  IMP compared to CE-2 diet containing 1.15% calcium fed Cyp27b1-KO ratsRGD 
Cyp27b1em1ThkaRatabnormal survival  IMP compared to CE-2 diet containing 1.15% calcium fed Cyp27b1-KO ratsRGD 
W-Cyp27b1em1ThkaRatabnormal survival penetranceIMPcontrolled content dietcompared to CE-2 diet containing 1.15% calcium fed Cyp27b1-KO ratsRGD 
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Genes (Rattus norvegicus)
Cyp27b1  (cytochrome P450, family 27, subfamily b, polypeptide 1) Cyp27b1em1Thka  (cytochrome P450, family 27, subfamily b, polypeptide 1; CRISPR/Cas9 induced mutant 1, Thka) Vdr  (vitamin D receptor)
Vdrem1Thka  (vitamin D receptor; CRISPR/Cas9 induced mutant 1, Thka) Vdrem2Thka  (vitamin D receptor; CRISPR/Cas9 induced mutant 2, Thka)

Genes (Mus musculus)
Cyp27b1  (cytochrome P450, family 27, subfamily b, polypeptide 1) Vdr  (vitamin D (1,25-dihydroxyvitamin D3) receptor)

Genes (Homo sapiens)
CYP27B1  (cytochrome P450 family 27 subfamily B member 1) VDR  (vitamin D receptor)

Strains
W-Cyp27b1em1Thka  (NA) W-Vdrem1Thka  (NA) W-Vdrem2Thka  (NA)