Abstract
Ezrin is a membrane-associated cytoplasmic protein that serves to link cell-membrane proteins with the actin-based cytoskeleton, and also plays a role in regulation of the functional activities of some transmembrane proteins. It is expressed in placental trophoblasts. We hypothesized that placental ezrin is involved in the supply of nutrients from mother to fetus, thereby influencing fetal growth. The aim of this study was firstly to clarify the effect of ezrin on fetal growth and secondly to determine whether knockout of ezrin is associated with decreased concentrations of serum and placental nutrients. Ezrin knockout mice (Ez−/−) were confirmed to exhibit fetal growth retardation. Metabolome analysis of fetal serum and placental extract of ezrin knockout mice by means of capillary electrophoresis–time-of-flight mass spectrometry revealed a markedly decreased concentration of hypotaurine, a precursor of taurine. However, placental levels of cysteine and cysteine sulfinic acid (precursors of hypotaurine) and taurine were not affected. Lack of hypotaurine in Ez−/− mice was confirmed by liquid chromatography with tandem mass spectrometry. Administration of hypotaurine to heterogenous dams significantly decreased the placenta-to-maternal plasma ratio of hypotaurine in wild-type fetuses but only slightly decreased it in ezrin knockout fetuses, indicating that the uptake of hypotaurine from mother to placenta is saturable and that disruption of ezrin impairs the uptake of hypotaurine by placental trophoblasts. These results indicate that ezrin is required for uptake of hypotaurine from maternal serum by placental trophoblasts, and plays an important role in fetal growth.
Highlights
In placenta, syncytiotrophoblasts form a continuous epithelial barrier and functionally regulate exchange of nutrients and waste products between the maternal and fetal circulations, namely, across the placental barrier
Protein expression of ezrin was observed on the maternal membrane side of syncytiotrophoblast layers in the labyrinth zone of Ez+/+ mouse placenta, while no immunofluorescence signals were observed at that site in Ez2/2 mouse (Figure 1B, 1C)
We investigated whether ezrin deficiency induced apoptosis, but few apoptotic cells were identified in the labyrinth zone of either Ez+/+ or Ez2/2 mouse placenta (Figure 2J, 2N), and differential interference contrast (DIC) microscopy revealed no marked differences (Figure 2K, 2O)
Summary
Syncytiotrophoblasts form a continuous epithelial barrier and functionally regulate exchange of nutrients and waste products between the maternal and fetal circulations, namely, across the placental barrier. Proper function of transporters at the syncytiotrophoblast is considered to be critical for fetal growth, because decreased activity of placental amino acid transporters is associated with intrauterine growth retardation [4,5]. Ezrin/radixin/moesin (ERM) proteins are membrane-associated cytoplasmic proteins that provide a regulated linkage between transmembrane proteins, including plasma membrane transporters, and cortical actin filaments. These linkages are crucial for organization and maintenance of specialized membrane domains, including the apical plasma membrane domain of epithelial cells [6,7]. Transporter/ ezrin complexes are considered to be important for the proper transport of physiological nutrients and metabolites in syncytiotrophoblast
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