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

Huaqin Sun,Kam Sze Tsang,Jieting Zhang,Huijuan Liao,Meng Mao,Xiaohua Jiang,Yanyan Liu,Wenming Xu,Kai Sheng,Hsiao Chang Chan,Ziyuan Lin,Yan Chen,Xiaohu Zhang,Yan Wang,Mingfeng Liu

doi:10.1038/s41419-018-0311-9

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.

Highlights

Cystic fibrosis transmembrane conductance regulator (CFTR) is an ATP-binding cassette (ABC) transporter superfamily cAMP-activated anion channel[1]
To further explore the role of Cftr in Wnt signaling during hematopoiesis, we further examined the effect of Cftr expression on key adaptors of the Wnt signaling, Dvls, in zebrafish
The present study has provided the first evidence for the involvement of CFTR in the regulation of Wnt-dependent hematopoiesis through its interaction with and regulation of the degradation process of a key adaptor protein of Wnt signaling, Dvl (Fig. 5e)

Summary

Introduction

Cystic fibrosis transmembrane conductance regulator (CFTR) is an ATP-binding cassette (ABC) transporter superfamily cAMP-activated anion channel[1]. Mutations of the CFTR have been shown to cause cystic fibrosis (CF), the most common lethal genetic disease in Caucasians with a hallmark defect in electrolyte and fluid transport affecting multiple organ systems with ion channel function due to the most common mutation of CFTR, ΔF508 mutation, has been shown to underline the pathogenesis of some of the disease conditions in CF, such as obstructive lung disease[5,6], pancreas exocrine deficiency[7], CF-related diabetes[8], abnormal gonad function, and infertility[9,10,11]. Accumulating evidence has indicated that, in addition to its channel function, CFTR may act as a potential regulator via its interaction with a large number of proteins[12]. Our previous study has found that CFTR interacts with adherens junction molecule AF-6/afadin via PDZBD,

Methods

Findings

Conclusion