title: Fetal growth retardation and lack of hypotaurine in ezrin knockout mice.
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.
authors.affiliation: Division of Pharmaceutics, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nishimura
authors.affiliation: Division of Pharmaceutics, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Higuchi
authors.affiliation: Division of Pharmaceutics, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, Japan; Department of Pharmacy, Kanazawa University Hospital, Kanazawa, Japan.
authors.forename: Yoshimichi
authors.initials: Y
authors.lastname: Sai
authors.affiliation: Division of Pharmaceutics, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Sugita
authors.affiliation: Division of Pharmaceutics, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Yoshida
authors.affiliation: Division of Pharmaceutics, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Tomi
authors.affiliation: Division of Pharmaceutics, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, Japan; Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Wada
authors.affiliation: Department of Histology and Embryology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Wakayama
authors.affiliation: Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tamura
authors.affiliation: Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Tsukita
authors.affiliation: Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan.
authors.forename: Tomoyoshi
authors.initials: T
authors.lastname: Soga
authors.affiliation: Division of Pharmaceutics, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, Japan.
authors.forename: Emi
authors.initials: E
authors.lastname: Nakashima
mesh_terms: D000818:Animals; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics* / Q000378:metabolism*; D018390:Gene Targeting; D056426:Genetic Loci; D006720:Homozygote; D007150:Immunohistochemistry; D055442:Metabolome; D055432:Metabolomics; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D010920:Placenta / Q000378:metabolism / Q000648:ultrastructure; D011247:Pregnancy; D013654:Taurine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000172:deficiency / Q000378:metabolism; D000099149:Ezrin
chemical_list: D003598:Cytoskeletal Proteins; D013654:Taurine; D000099149:Ezrin; C003949:hypotaurine