Essential Roles of L-Type Amino Acid Transporter 1 in Syncytiotrophoblast Development by Presenting Fusogenic 4F2hc.
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.
Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
Ryuichi
R
Ohgaki
Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
Takahiro
T
Ohmori
Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
Saori
S
Hara
Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
Saya
S
Nakagomi
Center of Experimental Animals, Tokyo Medical and Dental University, Tokyo, Japan.
Masami
M
Kanai-Azuma
Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
Kazuko
K
Kaneda-Nakashima
Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
Suguru
S
Okuda
Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
Shushi
S
Nagamori
Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan ykanai@pharma1.med.osaka-u.ac.jp.
Yoshikatsu
Y
Kanai
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002459:Cell Fusion; D002460:Cell Line; D019070:Cell Lineage; D049109:Cell Proliferation / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D003433:Crosses, Genetic; D020964:Embryo Loss / Q000473:pathology; D005260:Female; D027282:Fusion Regulatory Protein 1, Heavy Chain / Q000378:metabolism*; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D018390:Gene Targeting; D006720:Homozygote; D006801:Humans; D027283:Large Neutral Amino Acid-Transporter 1 / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010920:Placenta / Q000002:abnormalities / Q000187:drug effects; D011247:Pregnancy; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
D027282:Fusion Regulatory Protein 1, Heavy Chain; D027283:Large Neutral Amino Acid-Transporter 1; D005576:Colforsin
4F2 antigen; amino acid transporter; cell fusion; placenta; syncytiotrophoblast