Submission Number: KOU-4-17-13
Abstract Number: 519
INVOLVEMENT OF ALPHA TOCOPHEROL TRANSFER PROTEIN FOR THE DEVELOPMENT OF LABYRINTHINE TROPHOBLAST.
Kou-ichi Jishage 1, Makoto Arita 2, Keiji Igarashi 2, Hiroyuki Arai 2, Keizo Inoue 2 and Hiroshi Suzuki* 1
Pharmaceutical Technology Lab, Chugai Pharmaceutical Co., Ltd., Japan 1
Department of Health Chemistry, Graduate School of Pharmaceutical Sciences. University of Tokyo, Japan 2
Abstract:
Alpha-tocopherol transfer protein (alpha-TTP), which was identified as a product of the causative gene for the patients with ataxia with isolated vitamin E who suffer from progressive spinoceebellar dysfunction, is a cytosolic protein and specifically binds to alpha-tocopherol, and has the ability to transport alpha-tocopherol from liver to circulation. However, the physiological role of alpha-TTP gene in vivo has not been established yet. Thus, we generated mutant mice with a targeted disruption of the alpha-TTP gene. The targeting vector, in which the entire exon1 was replaced by a neomycin-resistance cassette to delete the initiation codon for alpha-TTP, was introduced into embryonic stem (ES) cells by electroporation and from ES cells into the mouse germline. When heterozygous mice were interbred, alpha-TTP-/- mutant mice were born at one-quarter (alpha-TTP+/+ : +/- : -/- = 63 : 105 : 74) the frequency expected for a recessive mutation. Both alpha-TTP+/- and alpha-TTP-/- mice were normal in appearance and growth. Alpha-TTP+/- and alpha-TTP-/- mice had undetectable and half levels of both alpha-tocopherol in serum and alpha-TTP mRNA in the liver as compared with alpha-TTP+/+ mice, respectively, indicating that the alpha-tocopherol concentration in the circulation is regulated by alpha-TTP expression levels. Male alpha-TTP-/- mice were fertile. However, the embryos in uterus of alpha-TTP-/- mice had severely impaired placentas with markedly reduction of labyrinthine trophoblasts, and died at midgestation (between 11.5 and 14.5 dpc), even if fertilized eggs from alpha-TTP+/+ mice were transferred into alpha-TTP-/- recipients. These results suggest a physiological role of alpha-TTP that is an essential factor for utilization of alpha-tocopherol for the development of labyrinthine trophobalsts.
Keywords: Labyrinthine trophobalsts Alpha-tocopherol transfer protein
This abstract is being presented at: 8:00 AM in session:
Implantation and Early Development