Slc20a2 deficiency results in fetal growth restriction and placental calcification associated with thickened basement membranes and novel CD13 and lamininα1 expressing cells

Abstract

The essential nutrient phosphorus must be taken up by the mammalian embryo during gestation. The mechanism(s) and key proteins responsible for maternal to fetal phosphate transport have not been identified. Established parameters for placental phosphate transport match those of the type III phosphate transporters, Slc20a1 and Slc20a2. Both members are expressed in human placenta, and their altered expression is linked to preeclampsia. In this study, we tested the hypothesis that Slc20a2 is required for placental function. Indeed, complete deficiency of Slc20a2 in either the maternal or embryonic placental compartment results in fetal growth restriction. We found that Slc20a2 null mice can reproduce, but are subviable; ~50% are lost prior to weaning age. We also observed that 23% of Slc20a2 deficient females develop pregnancy complications at full term, with tremors and placental abnormalities including abnormal vascular structure, increased basement membrane deposition, abundant calcification, and accumulation of novel CD13 and lamininα1 positive cells. Together these data support that Slc20a2 deficiency impacts both maternal and neonatal health, and Slc20a2 is required for normal placental function. In humans, decreased levels of placental Slc20a1 and Slc20a2 have been correlated with early onset preeclampsia, a disorder that can manifest from placental dysfunction. In addition, preterm placental calcification has been associated with poor pregnancy outcomes. We surveyed placental calcification in human preeclamptic placenta samples, and detected basement membrane-associated placental calcification as well as a comparable lamininα1 positive cell type, indicating that similar mechanisms may underlie both human and mouse placental calcification.

New Studies on Knockout Mouse for the SLC20A2 Gene Show Much More Than Brain Calcifications

“…More recently, Wallingford et al (2016b) found that this same model presents lower fetal viability, most likely due to abnormal placental function. This highlights that such models may help to elucidate multiple human conditions linked to inorganic phosphate homeostasis.…”

Murine Placental-Fetal Phosphate Dyshomeostasis Caused by an Xpr1 Deficiency Accelerates Placental Calcification and Restricts Fetal Growth in Late Gestation

“…(1,2) It plays a pivotal role in maternal-fetal nutrient transfer, and abnormal development or dysfunction of the placenta causes pathologies of pregnancy, such as fetal growth restriction, preeclampsia, and subsequent predisposition to lifelong illnesses. (1,2) It plays a pivotal role in maternal-fetal nutrient transfer, and abnormal development or dysfunction of the placenta causes pathologies of pregnancy, such as fetal growth restriction, preeclampsia, and subsequent predisposition to lifelong illnesses.…”

“…(12)(13)(14) NaPi-IIb expression in human/mouse placenta increases as placental development progresses, and NaPi-IIb is expressed in the fetomaternal interface of the placenta. (1,2) To the best of our knowledge, ectopic calcifications are always associated with Pi dyshomeostasis. (16) These data indicate that NaPi-IIb likely plays important roles in regulating placental-fetal Pi homeostasis.…”

“…T he placenta is a temporary organ with an extensive vascular network that connects the fetomaternal circulatory systems. (1,2) It plays a pivotal role in maternal-fetal nutrient transfer, and abnormal development or dysfunction of the placenta causes pathologies of pregnancy, such as fetal growth restriction, preeclampsia, and subsequent predisposition to lifelong illnesses. (3)(4)(5) Physiological inorganic phosphate (Pi), which is an essential nutrient for all living organisms, plays a crucial role in the placenta for fetal growth and metabolism and skeletal growth and development.…”

“…Slc20a1-deficient mice are embryonic-lethal during gestation, and Slc20a2 knockout mice show fetal growth restriction and severe placental calcification. (1,2) To the best of our knowledge, ectopic calcifications are always associated with Pi dyshomeostasis. (17) Similar to most ectopic calcifications, placental calcification mainly consists of calcium phosphate deposits.…”