The unfolded protein response (UPR) handles unfolded/misfolded proteins accumulated in the endoplasmic reticulum (ER). However, it is unclear how vertebrates correctly use the total of ten UPR transducers. We have found that ER stress occurs physiologically during early embryonic development in medaka fish and that the smooth alignment of notochord cells requires ATF6 as a UPR transducer, which induces ER chaperones for folding of type VIII (short-chain) collagen. After secretion of hedgehog for tissue patterning, notochord cells differentiate into sheath cells, which synthesize type II collagen. In this study, we show that this vacuolization step requires both ATF6 and BBF2H7 as UPR transducers and that BBF2H7 regulates a complete set of genes (Sec23/24/13/31, Tango1, Sedlin, and KLHL12) essential for the enlargement of COPII vesicles to accommodate long-chain collagen for export, leading to the formation of the perinotochordal basement membrane. Thus, the most appropriate UPR transducer is activated to cope with the differing physiological ER stresses of different content types depending on developmental stage.
Basic-Leucine Zipper Transcription Factors/metabolism , COP-Coated Vesicles/metabolism , Collagen Type II/metabolism , Fish Proteins/metabolism , Notochord/metabolism , Oryzias/metabolism , Unfolded Protein Response , Activating Transcription Factor 6/genetics , Activating Transcription Factor 6/metabolism , Animals , Animals, Genetically Modified , Basement Membrane/metabolism , Basic-Leucine Zipper Transcription Factors/genetics , Embryo, Nonmammalian/metabolism , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum Stress , Fish Proteins/genetics , Gene Expression Regulation, Developmental , Genotype , HCT116 Cells , Humans , Oryzias/embryology , Oryzias/genetics , Phenotype , Protein Transport , Time Factors , Transcription, Genetic , Transfection , Vacuoles/metabolism
We have investigated the effects of short-contact topical application of tretinoin using 16 male db/db mice by creating two full-thickness wounds on the skin of the back. A 0.1% tretinoin aqueous gel was applied to one wound for five minutes daily for five successive days while only aqueous gel was applied to the other (control). The mean (SD) percentage surface area unhealed before and after treatment were 0.88 (0.3) and 0.64 (0.15). In tretinoin-treated mice and non-treated mice (controls), the mean (SD) thicknesses of granulation were 1.383 (697) micro m and 683 (413) micro m, the density of capillary vessels in granulation was 12.2 (5.5)% and 5.7 (3.9)%, respectively. Differences between the two groups were significant for each variable. Wound healing was accelerated with short-contact topical application of tretinoin in db/db mice.
Keratolytic Agents/pharmacology , Tretinoin/pharmacology , Wound Healing/drug effects , Animals , Gels , Granulation Tissue/pathology , Keratolytic Agents/administration & dosage , Male , Mice , Mice, Inbred Strains , Tretinoin/administration & dosage , Wound Healing/physiology
