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ATF6?/?-mediated adjustment of ER chaperone levels is essential for development of the notochord in medaka fish.


ABSTRACT: ATF6? and ATF6? are membrane-bound transcription factors activated by regulated intramembrane proteolysis in response to endoplasmic reticulum (ER) stress to induce various ER quality control proteins. ATF6?- and ATF6? single-knockout mice develop normally, but ATF6?/? double knockout causes embryonic lethality, the reason for which is unknown. Here we show in medaka fish that ATF6? is primarily responsible for transcriptional induction of the major ER chaperone BiP and that ATF6?/? double knockout, but not ATF6?- or ATF6? 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 ATF6?- and ATF6?-mediated induction of BiP, and that knockdown of the ?1 chain of type VIII collagen reduces such ER stress. The absence of transcriptional induction of several ER chaperones in ATF6?/? double knockout causes more profound ER stress and impaired notochord development, which is partially rescued by overexpression of BiP. Thus ATF6?/?-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.

SUBMITTER: Ishikawa T 

PROVIDER: S-EPMC3639050 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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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 knock  ...[more]

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