PUBLICATION
CFTR mutation enhances Dishevelled degradation and results in impairment of Wnt-dependent hematopoiesis
- Authors
- Sun, H., Wang, Y., Zhang, J., Chen, Y., Liu, Y., Lin, Z., Liu, M., Sheng, K., Liao, H., Tsang, K.S., Zhang, X., Jiang, X., Xu, W., Mao, M., Chan, H.C.
- ID
- ZDB-PUB-180223-25
- Date
- 2018
- Source
- Cell Death & Disease 9: 275 (Journal)
- Registered Authors
- Chan, Hsiao Chang, Sun, Huaqin
- Keywords
- none
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Cystic Fibrosis Transmembrane Conductance Regulator/genetics*
- Cystic Fibrosis Transmembrane Conductance Regulator/metabolism
- Dishevelled Proteins/genetics
- Dishevelled Proteins/metabolism
- Gene Expression Regulation, Developmental
- Hematopoiesis*
- Humans
- Intracellular Signaling Peptides and Proteins/metabolism
- Lysosomes/metabolism
- Membrane Proteins/genetics
- Membrane Proteins/metabolism*
- Mutation*
- PDZ Domains
- Proteolysis
- Wnt Signaling Pathway*
- Zebrafish/embryology
- Zebrafish/genetics
- Zebrafish/metabolism*
- Zebrafish Proteins/genetics*
- Zebrafish Proteins/metabolism*
- beta Catenin/genetics
- beta Catenin/metabolism
- PubMed
- 29449653 Full text @ Cell Death Dis.
Citation
Sun, H., Wang, Y., Zhang, J., Chen, Y., Liu, Y., Lin, Z., Liu, M., Sheng, K., Liao, H., Tsang, K.S., Zhang, X., Jiang, X., Xu, W., Mao, M., Chan, H.C. (2018) CFTR mutation enhances Dishevelled degradation and results in impairment of Wnt-dependent hematopoiesis. Cell Death & Disease. 9:275.
Abstract
Mutations of cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis (CF) with a multitude of clinical manifestations. Some CF patients develop clinically significant anemia, suggesting that CFTR may regulate hematopoiesis. Here, we report that cftr mutant zebrafish model exhibits primitive and definitive hematopoietic defects with impaired Wnt signaling. Cftr is found to interact, via its PDZ-binding domain (PDZBD), with Dishevelled (Dvl), a key component of Wnt signaling required for hematopoietic progenitor specification, thus protecting Dvl from Dapper1 (Dpr1)-induced lysosomal degradation. Defective hematopoiesis and impaired Wnt signaling in cftr mutant can be rescued by overexpression of wild-type or channel function-defective G551D mutant CFTR with an intact PDZBD, but not Cftr with mutations in the PDZBD. Analysis of human database ( http://r2.amc.nl ) shows that CFTR is positively correlated with DVL2 and Wnt-related hematopoietic factors in human blood system. The results reveal a previously unrecognized role of CFTR, which is independent of its channel function, in regulating DVL degradation and thus Wnt signaling required for hematopoiesis in both zebrafish and humans, providing an explanation for the anemic phenotype of CF patients.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping