Search

We utilized a vitamin D receptor (VDR) gene knockout model to study the effects of maternal and fetal absence of VDR on maternal fertility, fetal-placental calcium transfer, and fetal mineral homoeostasis. Vdr null mice were profoundly hypocalcemic, conceived infrequently, and had significantly fewer viable fetuses in utero that were also of lower body weight. Supplementation of a calcium-enriched diet increased the rate of conception in Vdr nulls but did not normalize the number or weight of viable fetuses. Among offspring of heterozygous (Vdr(+/-)) mothers (wild type, Vdr(+/-), and Vdr null fetuses), there was no alteration in serum Ca, P, or Mg, parathyroid hormone, placental (45)Ca transfer, Ca and Mg content of the fetal skeleton, and morphology and gene expression in the fetal growth plates. Vdr null fetuses did have threefold increased 1,25-dihydroxyvitamin D levels accompanied by increased 1alpha-hydroxylase mRNA in kidney but not placenta; a small increase was also noted in placental expression of parathyroid hormone-related protein (PTHrP). Among offspring of Vdr null mothers, Vdr(+/-) and Vdr null fetuses had normal ionized calcium levels and a skeletal ash weight that was appropriate to the lower body weight. Thus our findings indicate that VDR is not required by fetal mice to regulate placental calcium transfer, circulating mineral levels, and skeletal mineralization. Absence of maternal VDR has global effects on fetal growth that were partly dependent on maternal calcium intake, but absence of maternal VDR did not specifically affect fetal mineral homeostasis.

The expression of calcitropic genes and proteins was localized within murine placenta during late gestation (the time frame of active calcium transfer) with an analysis of several gene-deletion mouse models by immunohistochemistry and in situ hybridization. Parathyroid hormone-related protein (PTHrP), the PTH/PTHrP receptor, calcium receptor, calbindin-D(9k), Ca(2+)-ATPase, and vitamin D receptor were all highly expressed in a localized structure of the murine placenta, the intraplacental yolk sac, compared with trophoblasts. In the PTHrP gene-deleted or Pthrp-null placenta in which placental calcium transfer is decreased, calbindin-D(9k) expression was downregulated in the intraplacental yolk sac but not in the trophoblasts. These observations indicated that the intraplacental yolk sac contains calcium transfer and calcium-sensing capability and that it is a probable route of maternal-fetal calcium exchange in the mouse.

A transport protein is described with 12 transmembrane spans. Within the cytoplasmic amino-terminal domain, several novel hexad repeats are conserved in human, mouse, rat and pig, four to six of which had the canonical form PS_S_H+. In the carboxyl-terminal domain, a polyglutamate sequence (5–8) is conserved. Restricted expression of the transporter was identified in acidophil cells of the adult pituitary that secrete growth hormone and prolactin. In the fetus, expression was restricted to osteoclasts, chondrocytes, thyroid, pituitary, central nervous system, eye, liver and heart. In particular, expression was found in structures associated with rapid calcium exchange including the retina, cardiomyocytes and in the intraplacental yolk sac that expresses calcitropic molecules. Furthermore, expression found in osteoclasts and kidney, within the distal portions of nephrons and collecting ducts, was consistent with a role in calcium homeostasis. In human pituitary, four mRNA transcripts, and in mouse kidney, three mRNA transcripts were expressed. In developing mouse kidney, the amount of each transcript varied that suggested the multiple transcripts might be differentially expressed in different physiological states. We propose that the transporter is specific for a calcium-chelator complex and is important for growth and calcium metabolism. [Copyright &y& Elsevier]