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

  

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal 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 
VdrRatabnormal trabecular bone morphology  IMP  RGD 
Vdrem1ThkaRatabnormal trabecular bone morphology  IMP  RGD 
Vdrem2ThkaRatabnormal trabecular bone morphology  IMP  RGD 
W-Vdrem1ThkaRatabnormal trabecular bone morphology  IMP  RGD 
W-Vdrem2ThkaRatabnormal trabecular bone morphology  IMP  RGD 
VdrRatalopecia  IMP  RGD 
Vdrem2ThkaRatalopecia  IMP  RGD 
W-Vdrem2ThkaRatalopecia  IMP  RGD 
Cyp27b1Ratdecreased body height  IMP  RGD 
Cyp27b1em1ThkaRatdecreased body height  IMP  RGD 
W-Cyp27b1em1ThkaRatdecreased body height  IMP  RGD 
Cyp27b1Ratdecreased circulating calcium level treatmentIMPvitamin D3compared to Jcl:Wi and untreatedRGD 
Cyp27b1em1ThkaRatdecreased circulating calcium level treatmentIMPvitamin D3compared to Jcl:Wi and untreatedRGD 
VdrRatdecreased circulating calcium level treatmentIMPvitamin D3compared to Jcl:Wi and untreatedRGD 
Vdrem1ThkaRatdecreased circulating calcium level treatmentIMPvitamin D3compared to Jcl:Wi and untreatedRGD 
W-Cyp27b1em1ThkaRatdecreased circulating calcium level treatmentIMPvitamin D3compared to Jcl:Wi and untreatedRGD 
W-Vdrem1ThkaRatdecreased circulating calcium level treatmentIMPvitamin D3compared to Jcl:Wi and untreatedRGD 
Cyp27b1Ratincreased body weight treatmentIMPvitamin D3compared to untreatedRGD 
Cyp27b1em1ThkaRatincreased body weight treatmentIMPvitamin D3compared to untreatedRGD 
W-Cyp27b1em1ThkaRatincreased body weight treatmentIMPvitamin D3compared to untreatedRGD 
Cyp27b1Ratincreased bone mineral density of femur treatmentIMPvitamin D3compared to Jcl:Wi and untreatedRGD 
Cyp27b1em1ThkaRatincreased bone mineral density of femur treatmentIMPvitamin D3compared to Jcl:Wi and untreatedRGD 
W-Cyp27b1em1ThkaRatincreased bone mineral density of femur treatmentIMPvitamin D3compared to Jcl:Wi and untreatedRGD 
Cyp27b1Ratincreased circulating parathyroid hormone level treatmentIMPvitamin D3compared to Jcl:Wi and treatedRGD 
Cyp27b1em1ThkaRatincreased circulating parathyroid hormone level treatmentIMPvitamin D3compared to Jcl:Wi and treatedRGD 
VdrRatincreased circulating parathyroid hormone level treatmentIMPvitamin D3compared to Jcl:Wi and treatedRGD 
VdrRatincreased circulating parathyroid hormone level  IMPvitamin D3 RGD 
Vdrem1ThkaRatincreased circulating parathyroid hormone level treatmentIMPvitamin D3compared to Jcl:Wi and treatedRGD 
Vdrem2ThkaRatincreased circulating parathyroid hormone level  IMPvitamin D3 RGD 
W-Cyp27b1em1ThkaRatincreased circulating parathyroid hormone level treatmentIMPvitamin D3compared to Jcl:Wi and treatedRGD 
W-Vdrem1ThkaRatincreased circulating parathyroid hormone level treatmentIMPvitamin D3compared to Jcl:Wi and treatedRGD 
W-Vdrem2ThkaRatincreased circulating parathyroid hormone level  IMPvitamin D3 RGD 
VdrRatnephrolithiasis  IMP  RGD 
Vdrem2ThkaRatnephrolithiasis  IMP  RGD 
W-Vdrem2ThkaRatnephrolithiasis  IMP  RGD 
Cyp27b1Ratosteomalacia treatmentIMPvitamin D3compared to Jcl:Wi and treatedRGD 
Cyp27b1em1ThkaRatosteomalacia treatmentIMPvitamin D3compared to Jcl:Wi and treatedRGD 
VdrRatosteomalacia  IMP  RGD 
Vdrem1ThkaRatosteomalacia  IMP  RGD 
W-Cyp27b1em1ThkaRatosteomalacia treatmentIMPvitamin D3compared to Jcl:Wi and treatedRGD 
W-Vdrem1ThkaRatosteomalacia  IMP  RGD 
Objects Annotated

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)


Additional Information