Essential Roles of L-Type Amino Acid Transporter 1 in Syncytiotrophoblast Development by Presenting Fusogenic 4F2hc

Abstract

The layers of the epithelial syncytium, i.e., syncytiotrophoblasts, differentiate from chorionic trophoblasts via cell fusion and separate maternal and fetal circulations in hemochorial placentas. L-type amino acid transporter 1 (LAT1) and its covalently linked ancillary subunit 4F2hc are colocalized on both maternal and fetal surfaces of syncytiotrophoblasts, implying their roles in amino acid transfer through the placental barrier. In this study, LAT1 knockout, in addition, revealed a novel role of LAT1 in syncytiotrophoblast development. LAT1 at midgestation was selectively expressed in trophoblastic lineages in the placenta, exclusively as a LAT1-4F2hc heterodimer. In LAT1 homozygous knockout mice, chorionic trophoblasts remained largely mononucleated, and the layers of syncytiotrophoblasts were almost completely absent. The amount of 4F2hc protein, which possesses a fusogenic function in trophoblastic cells, as well as in virus-infected cells, was drastically reduced by LAT1 knockout, with less affecting the mRNA level. Knockdown of LAT1 in trophoblastic BeWo cells also reduced 4F2hc protein and suppressed forskolin-induced cell fusion. These results demonstrate a novel fundamental role of LAT1 to support the protein expression of 4F2hc via a chaperone-like function in chorionic trophoblasts and to promote syncytiotrophoblast formation by contributing to cell fusion in the developing placenta.

RNA-Seq identifies genes whose proteins are transformative in the differentiation of cytotrophoblast to syncytiotrophoblast, in human primary villous and BeWo trophoblasts

“…ROCK1 and RAC1 40 were expressed at similar levels across all time points and treatments. Both LAT1 and 4F2hc 41 were upregulated 3–4 fold in forskolin-treated BeWo cells at 72 hours. In human placental cells, there was little change in transcript levels for these two genes.…”

Methionine Partially Replaced by Methionyl-Methionine Dipeptide Improves Reproductive Performance over Methionine Alone in Methionine-Deficient Mice

“…In the present study, the abundance of AA transporters in the placenta was consistent with the AA concentrations of the fetal blood of the three groups. Many of the AA transporters were analyzed, including system A (SLC38A1, SLC38A2 and SLC38A4), which accounts for most Na + -dependent neutral amino acid uptake by mammalian cells [ 25 ], and system L (SLC7A8), which mainly transports large branched and aromatic neutral amino acids [ 26 ], showed lower mRNA abundance levels in the 35% Met group and higher abundance levels in the 25% Met-Met group.…”

The Human SLC7A5 (LAT1): The Intriguing Histidine/Large Neutral Amino Acid Transporter and Its Relevance to Human Health

“…This function is mediated by other high capacity transport systems located in the microvilli brush-border (Bröer and Bröer, 2017 ). An important evidence of the crucial role of LAT1 in cell metabolism and growth derives from the lethal phenotype of knockout animal embryo, which cannot go beyond the mid-gestation stage (E11.5), i.e., when nervous cells start to differentiate (Ohgaki et al, 2017 ). Over the years, the interest around this transporter moved from biochemical to bio-medical issues due to its involvement in important diseases such as cancer and neurological disorders (Fuchs and Bode, 2005 ; del Amo et al, 2008 ).…”