CFTR mutation enhances Dishevelled degradation and results in impairment of Wnt-dependent hematopoiesis.

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.

• Authors: Huaqin Sun, Yan Wang, Jieting Zhang, Yan Chen, Yanyan Liu, Ziyuan Lin, Mingfeng Liu, Kai Sheng, Huijuan Liao, Kam Sze Tsang, Xiaohu Zhang, Xiaohua Jiang, Wenming Xu, Meng Mao, Hsiao Chang Chan
• Journal: Cell death & disease (Cell Death Dis) Vol. 9 Issue 3 Pg. 275 (02 15 2018) ISSN: 2041-4889 [Electronic] England
• PMID: 29449653 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CFTR protein, human
• CFTR protein, zebrafish
• CTNNB1 protein, human
• DVL2 protein, human
• Dishevelled Proteins
• Dvl2 protein, zebrafish
• Intracellular Signaling Peptides and Proteins
• Membrane Proteins
• Zebrafish Proteins
• beta Catenin
• dact1 protein, zebrafish
• Cystic Fibrosis Transmembrane Conductance Regulator

Topics

• Animals
• Animals, Genetically Modified
• Cystic Fibrosis Transmembrane Conductance Regulator (genetics, metabolism)
• Dishevelled Proteins (genetics, metabolism)
• Gene Expression Regulation, Developmental
• Hematopoiesis
• Humans
• Intracellular Signaling Peptides and Proteins (metabolism)
• Lysosomes (metabolism)
• Membrane Proteins (genetics, metabolism)
• Mutation
• PDZ Domains
• Proteolysis
• Wnt Signaling Pathway
• Zebrafish (embryology, genetics, metabolism)
• Zebrafish Proteins (genetics, metabolism)
• beta Catenin (genetics, metabolism)