The α-tocopherol transfer protein is essential for vertebrate embryogenesis.
The hepatic α-tocopherol transfer protein (TTP) is required for optimal α-tocopherol bioavailability in humans; mutations in the human TTPA gene result in the heritable disorder ataxia with vitamin E deficiency (AVED, OMIM #277460). TTP is also expressed in mammalian uterine and placental cells and in the human embryonic yolk-sac, underscoring TTP's significance during fetal development. TTP and vitamin E are essential for productive pregnancy in rodents, but their precise physiological role in embryogenesis is unknown. We hypothesize that TTP is required to regulate delivery of α-tocopherol to critical target sites in the developing embryo. We tested to find if TTP is essential for proper vertebrate development, utilizing the zebrafish as a non-placental model. We verify that TTP is expressed in the adult zebrafish and its amino acid sequence is homologous to the human ortholog. We show that embryonic transcription of TTP mRNA increases >7-fold during the first 24 hours following fertilization. In situ hybridization demonstrates that Ttpa transcripts are localized in the developing brain, eyes and tail bud at 1-day post fertilization. Inhibiting TTP expression using oligonucleotide morpholinos results in severe malformations of the head and eyes in nearly all morpholino-injected embryos (88% compared with 5.6% in those injected with control morpholinos or 1.7% in non-injected embryos). We conclude that TTP is essential for early development of the vertebrate central nervous system.
Linus Pauling Institute, Oregon State University, Corvallis, Oregon, United States of America.
Galen W
GW
Miller
Lynn
L
Ulatowski
Edwin M
EM
Labut
Katie M
KM
Lebold
Danny
D
Manor
Jeffrey
J
Atkinson
Carrie L
CL
Barton
Robert L
RL
Tanguay
Maret G
MG
Traber
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D002490:Central Nervous System / Q000254:growth & development; D047108:Embryonic Development / Q000235:genetics* / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D014714:Vertebrates / Q000235:genetics / Q000254:growth & development; D014810:Vitamin E / Q000235:genetics / Q000378:metabolism*; D014811:Vitamin E Deficiency / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development*; D024502:alpha-Tocopherol / Q000378:metabolism*
D002352:Carrier Proteins; C017763:alpha-tocopherol transfer protein; D014810:Vitamin E; D024502:alpha-Tocopherol