CFTR- β -catenin interaction regulates mouse embryonic stem cell differentiation and embryonic development

Abstract

Cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-regulated anion channel capable of conducting both Cl and HCO, mutations of which cause cystic fibrosis (CF), a common autosomal recessive disease. Although CF patients are known to have varied degree of developmental problems, the biological role of CFTR in embryonic development remains elusive. Here, we show that CFTR is functionally expressed in mouse ESCs. CFTR mESCs exhibit dramatic defect in mesendoderm differentiation. In addition, CFTR physically interacts with β-catenin, defect of which leads to premature degradation of β-catenin and suppressed activation of β-catenin signaling. Furthermore, knockdown of CFTR retards the early development of Xenopus laevis with impaired mesoderm/endoderm differentiation and β-catenin signaling. Our study reveals a previously undefined role of CFTR in controlling ESC differentiation and early embryonic development via its interaction with β-catenin, and provides novel insights into the understanding of embryonic development.

What Role Does CFTR Play in Development, Differentiation, Regeneration and Cancer?

“…The Wnt/β-cat signalling pathway has a central role in controlling proliferation and lineage specification during early embryogenesis. CFTR appears to be critical for early embryonic development by regulating β-cat-associated pathways in vivo [8]. Additional results from mouse embryonic stem cells (mESCs) point to a role of CFTR in early mesendoderm differentiation, by interacting with β-cat and preventing its phosphorylation and premature degradation [8].…”

“…CFTR appears to be critical for early embryonic development by regulating β-cat-associated pathways in vivo [8]. Additional results from mouse embryonic stem cells (mESCs) point to a role of CFTR in early mesendoderm differentiation, by interacting with β-cat and preventing its phosphorylation and premature degradation [8]. The loss of CFTR is proposed to result in suppression of β-cat transcriptional activity affecting Wnt signalling that is instrumental in mesendoderm induction [8].…”

“…Additional results from mouse embryonic stem cells (mESCs) point to a role of CFTR in early mesendoderm differentiation, by interacting with β-cat and preventing its phosphorylation and premature degradation [8]. The loss of CFTR is proposed to result in suppression of β-cat transcriptional activity affecting Wnt signalling that is instrumental in mesendoderm induction [8]. Interestingly, wt-CFTR itself is known to interact with several components of the Wnt signalling pathway, an association which is lost for F508del-CFTR [69].…”

“…In parallel with cancer, an increasing number of emerging studies show that CFTR plays a role in fundamental cellular processes such as foetal development [4][5][6][7][8][9], epithelial differentiation/ polarization [10][11][12][13][14], regeneration [15][16][17], and epithelial-mesenchymal transition (EMT) [18][19][20][21][22] (Figure 1).…”

CFTR is required for the migration of primordial germ cells during zebrafish early embryogenesis

“…Besides the roles in differentiated germ cells, CFTR also plays an important role in embryo development as an ion channel ( Lu et al 2012 , 2016 ). Intriguingly, apart from its ion channel function, CFTR can also serve as a protein interaction hub and modulate the differentiation of embryonic stem cells via its interaction with β-catenin ( Liu et al 2017 ). The demonstrated roles of CFTR in primitive stem cells and germ cells prompted us to investigate the potential involvement of CFTR in regulating the development of the most primitive type of germ cells, the primordial germ cells (PGCs).…”