Loss of the sulfate transporter Slc13a4 in placenta causes severe fetal abnormalities and death in mice

Sulfate is an obligate nutrient for numerous cellular and metabolic processes important for fetal development¹. Fetal tissues express sulfotransferases which conjugate sulfate (sulfonate) to molecules such as steroids and hormones, leading to their inactivation². In addition, sulfonation of glycosaminoglycans is important for development of some tissues, as several growth factor gradients and ligand-receptor interactions are dependent on these sulfonated extracellular constituents³. Not surprisingly therefore, reduced sulfonation capacity has been linked to disorders of skeletal, eye, vascular and craniofacial development, demonstrating a critical requirement for sulfate in these tissues⁴. Despite a fundamental role for sulfate during development, the fetus appears to have a limited capacity to generate sulfate from sulfur-containing amino acids, and is thought to be reliant on maternal sulfate provision⁵. In fact, maternal serum sulfate levels increase two-fold during pregnancy, and provide a potential reservoir for fetal consumption^6,7. The elevated sulfate levels are due to increased sulfate reabsorption in the maternal kidneys, mediated by increased expression of the SLC13A1 sulfate transporter⁷. The importance of maintaining high maternal sulfate levels in pregnancy is highlighted by the hyposulfatemia seen in pregnant Slc13a1^−/− mice, which causes fetal hyposulfatemia and late gestational fetal loss.

Despite its importance in fetal development, relatively little is known about how sulfate traverses the placenta. The sulfate transporter SLC13A4 is expressed predominantly in the placenta, where it is proposed to mediate sulfate supply to the fetus⁸. Previously we examined the spatial localization of all 10 sulfate transporters in human⁹ and mouse placenta⁸ and identified Slc13a4 as the most abundant sulfate transporter localized to the transporting syncytiotrophoblasts. In the current study we describe the critical requirement of placental Slc13a4 activity for normal fetal development in mice.

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