RRC ID 31353
Author Ishikawa T, Okada T, Ishikawa-Fujiwara T, Todo T, Kamei Y, Shigenobu S, Tanaka M, Saito TL, Yoshimura J, Morishita S, Toyoda A, Sakaki Y, Taniguchi Y, Takeda S, Mori K.
Title ATF6α/β-mediated adjustment of ER chaperone levels is essential for development of the notochord in medaka fish.
Journal Mol Biol Cell
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.
Volume 24(9)
Pages 1387-95
Published 2013-5-1
DOI 10.1091/mbc.E12-11-0830
PII mbc.E12-11-0830
PMID 23447699
PMC PMC3639050
MeSH Activating Transcription Factor 6 / genetics Activating Transcription Factor 6 / metabolism* Amino Acid Sequence Animals Endoplasmic Reticulum / metabolism* Endoplasmic Reticulum Chaperone BiP Endoplasmic Reticulum Stress Female Fish Proteins / genetics Fish Proteins / metabolism* Gene Knockout Techniques Genes, Lethal Heat-Shock Proteins / chemistry Heat-Shock Proteins / genetics Heat-Shock Proteins / metabolism* Male Molecular Sequence Data Notochord / embryology* Notochord / metabolism Oryzias / embryology* Oryzias / metabolism Point Mutation RNA Splicing Transcriptional Activation
IF 3.791
Times Cited 32
Medaka TG998 TG999 TG1000 TG1001 TG1002