ZFIN ID: ZDB-PUB-161224-23
Impairment of Cargo Transportation Caused by gbf1 Mutation Disrupts Vascular Integrity and Causes Hemorrhage in Zebrafish Embryos.
Chen, J., Wu, X., Yao, L., Yan, L., Zhang, L., Qiu, J., Liu, X., Jia, S., Meng, A.
Date: 2017
Source: The Journal of biological chemistry 292(6): 2315-2327 (Journal)
Registered Authors: Chen, Jing, Jia, Shunji, Meng, Anming, Qiu, Juhui
Keywords: Golgi, embryo, protein trafficking (Golgi), vascular, zebrafish
Microarrays: GEO:GSE83987
MeSH Terms:
  • Animals
  • Blood Vessels/physiopathology*
  • Coat Protein Complex I/metabolism
  • Golgi Apparatus/metabolism
  • Guanine Nucleotide Exchange Factors/genetics*
  • Guanine Nucleotide Exchange Factors/metabolism
  • Hemorrhage/etiology*
  • Mutation*
  • Protein Transport
  • Zebrafish/embryology*
PubMed: 28003365 Full text @ J. Biol. Chem.
FIGURES
ABSTRACT
ADP-ribosylation factor GTPases are activated by guanine nucleotide exchange factors including Gbf1 (Golgi brefeldin A-resistant factor 1) and play important roles in regulating organelle structure and cargo-selective vesicle trafficking. However, the developmental role of Gbf1 in vertebrates remains elusive. In this study, we report the zebrafish mutant line tsu3994 that arises from N-ethyl-N-nitrosourea (ENU)-mediated mutagenesis and is characterized by prominent intracerebral and trunk hemorrhage. The mutant embryos develop hemorrhage accompanied by fewer pigments and shorter caudal fin at day 2 of development. The hemorrhage phenotype is caused by vascular breakage in a cell autonomous fashion. Positional cloning identifies a T → G nucleotide substitution in the 23rd exon of the gbf1 locus, resulting in a leucine → arginine substitution (L1246R) in the HDS2 domain. The mutant phenotype is mimicked by gbf1 knockouts and morphants, suggesting a nature of loss of function. Experimental results in mammalian cells show that the mutant form Gbf1(L1246R) is unable to be recruited to the Golgi apparatus and fails to activate Arf1 for recruiting COPI complex. The hemorrhage in tsu3994 mutants can be prevented partially and temporally by treating with the endoplasmic reticulum stress/apoptosis inhibitor tauroursodeoxycholic acid or by knocking down the proapoptotic gene baxb Therefore, endothelial endoplasmic reticulum stress and subsequent apoptosis induced by gbf1 deficiency may account for the vascular collapse and hemorrhage.
ADDITIONAL INFORMATIONNo data available