ATF6α/β-mediated Adjustment of ER Chaperone Levels Is Essential for Development of the Notochord in Medaka Fish

ATF6α and ATF6β are membrane-bound transcription factors which are 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 remains unknown. Here, we showed 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 revealed that ER stress occurred 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 α1 chain of type VIII collagen reduced such ER stress. The absence of transcriptional induction of several ER chaperones in ATF6α/β-double knockout caused more profound ER stress and impaired notochord development, which was 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 prior to formation of the vertebra.