PUBLICATION

Impairment of Cargo Transportation Caused by gbf1 Mutation Disrupts Vascular Integrity and Causes Hemorrhage in Zebrafish Embryos.

Authors
Chen, J., Wu, X., Yao, L., Yan, L., Zhang, L., Qiu, J., Liu, X., Jia, S., Meng, A.
ID
ZDB-PUB-161224-23
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
Datasets
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.
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.
Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes