title: Vitamin D Receptor Gene Ablation in the Conceptus Has Limited Effects on Placental Morphology, Function and Pregnancy Outcome.
abstract: Vitamin D deficiency has been implicated in the pathogenesis of several pregnancy complications attributed to impaired or abnormal placental function, but there are few clues indicating the mechanistic role of vitamin D in their pathogenesis. To further understand the role of vitamin D receptor (VDR)-mediated activity in placental function, we used heterozygous Vdr ablated C57Bl6 mice to assess fetal growth, morphological parameters and global gene expression in Vdr null placentae. Twelve Vdr+/- dams were mated at 10-12 weeks of age with Vdr+/- males. At day 18.5 of the 19.5 day gestation in our colony, females were euthanised and placental and fetal samples were collected, weighed and subsequently genotyped as either Vdr+/+, Vdr+/- or Vdr-/-. Morphological assessment of placentae using immunohistochemistry was performed and RNA was extracted and subject to microarray analysis. This revealed 25 genes that were significantly differentially expressed between Vdr+/+ and Vdr-/- placentae. The greatest difference was a 6.47-fold change in expression of Cyp24a1 which was significantly lower in the Vdr-/- placentae (P<0.01). Other differentially expressed genes in Vdr-/- placentae included those involved in RNA modification (Snord123), autophagy (Atg4b), cytoskeletal modification (Shroom4), cell signalling (Plscr1, Pex5) and mammalian target of rapamycin (mTOR) signalling (Deptor and Prr5). Interrogation of the upstream sequence of differentially expressed genes identified that many contain putative vitamin D receptor elements (VDREs). Despite the gene expression differences, this did not contribute to any differences in overall placental morphology, nor was function affected as there was no difference in fetal growth as determined by fetal weight near term. Given our dams still expressed a functional VDR gene, our results suggest that cross-talk between the maternal decidua and the placenta, as well as maternal vitamin D status, may be more important in determining pregnancy outcome than conceptus expression of VDR.
authors.affiliation: Robinson Research Institute, Adelaide, Australia; School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, Australia.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Wilson
authors.affiliation: Robinson Research Institute, Adelaide, Australia; School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, Australia.
authors.forename: Sam
authors.initials: S
authors.lastname: Buckberry
authors.affiliation: Robinson Research Institute, Adelaide, Australia; School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, Australia.
authors.forename: Fleur
authors.initials: F
authors.lastname: Spronk
authors.affiliation: Robinson Research Institute, Adelaide, Australia; School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, Australia.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Laurence
authors.affiliation: Robinson Research Institute, Adelaide, Australia; School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, Australia.
authors.forename: Shalem
authors.initials: S
authors.lastname: Leemaqz
authors.affiliation: Robinson Research Institute, Adelaide, Australia; School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, Australia.
authors.forename: Sean
authors.initials: S
authors.lastname: O'Leary
authors.affiliation: Robinson Research Institute, Adelaide, Australia; School of Agriculture, Food and Wine, University of Adelaide, Adelaide, Australia.
authors.forename: Tina
authors.initials: T
authors.lastname: Bianco-Miotto
authors.affiliation: Robinson Research Institute, Adelaide, Australia; Shanghai Institute of Planned Parenthood Research, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Du
authors.affiliation: School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, Adelaide, Australia.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Anderson
authors.affiliation: Robinson Research Institute, Adelaide, Australia; School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, Australia.
authors.forename: Claire T
authors.initials: CT
authors.lastname: Roberts
mesh_terms: D000818:Animals; D005260:Female; D005333:Fetus / Q000378:metabolism*; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005838:Genotype; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D010920:Placenta / Q000033:anatomy & histology* / Q000378:metabolism / Q000502:physiology*; D011247:Pregnancy; D011256:Pregnancy Outcome / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D018167:Receptors, Calcitriol / Q000235:genetics*; D015203:Reproducibility of Results; D059467:Transcriptome / Q000235:genetics; D065668:Vitamin D3 24-Hydroxylase / Q000235:genetics
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D018167:Receptors, Calcitriol; C570841:deptor protein, mouse; D065668:Vitamin D3 24-Hydroxylase