title: ATF6α/β-mediated adjustment of ER chaperone levels is essential for development of the notochord in medaka fish.
abstract: ATF6α and ATF6β are membrane-bound transcription factors activated by regulated intramembrane proteolysis in response to endoplasmic reticulum (ER) stress to induce various ER quality control proteins. ATF6α- and ATF6β single-knockout mice develop normally, but ATF6α/β double knockout causes embryonic lethality, the reason for which is unknown. Here we show in medaka fish that ATF6α is primarily responsible for transcriptional induction of the major ER chaperone BiP and that ATF6α/β double knockout, but not ATF6α- or ATF6β single knockout, causes embryonic lethality, as in mice. Analyses of ER stress reporters reveal that ER stress occurs physiologically during medaka early embryonic development, particularly in the brain, otic vesicle, and notochord, resulting in ATF6α- and ATF6β-mediated induction of BiP, and that knockdown of the α1 chain of type VIII collagen reduces such ER stress. The absence of transcriptional induction of several ER chaperones in ATF6α/β double knockout causes more profound ER stress and impaired notochord development, which is partially rescued by overexpression of BiP. Thus ATF6α/β-mediated adjustment of chaperone levels to increased demands in the ER is essential for development of the notochord, which synthesizes and secretes large amounts of extracellular matrix proteins to serve as the body axis before formation of the vertebra.
authors: Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan.
authors: Tokiro
authors: T
authors: Ishikawa
authors: Tetsuya
authors: T
authors: Okada
authors: Tomoko
authors: T
authors: Ishikawa-Fujiwara
authors: Takeshi
authors: T
authors: Todo
authors: Yasuhiro
authors: Y
authors: Kamei
authors: Shuji
authors: S
authors: Shigenobu
authors: Minoru
authors: M
authors: Tanaka
authors: Taro L
authors: TL
authors: Saito
authors: Jun
authors: J
authors: Yoshimura
authors: Shinichi
authors: S
authors: Morishita
authors: Atsushi
authors: A
authors: Toyoda
authors: Yoshiyuki
authors: Y
authors: Sakaki
authors: Yoshihito
authors: Y
authors: Taniguchi
authors: Shunichi
authors: S
authors: Takeda
authors: Kazutoshi
authors: K
authors: Mori
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D005260:Female; D029941:Fish Proteins / Q000235:genetics / Q000378:metabolism*; D055786:Gene Knockout Techniques; D005804:Genes, Lethal; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D009672:Notochord / Q000196:embryology* / Q000378:metabolism; D009990:Oryzias / Q000196:embryology* / Q000378:metabolism; D017354:Point Mutation; D012326:RNA Splicing; D015533:Transcriptional Activation
chemical_list: D051702:Activating Transcription Factor 6; D000091342:Endoplasmic Reticulum Chaperone BiP; D029941:Fish Proteins; D006360:Heat-Shock Proteins