title: Apc deficiency alters pulmonary epithelial cell fate and inhibits Nkx2.1 via triggering TGF-beta signaling.
abstract: Wnt signaling is critical for cell fate specification and cell differentiation in many organs, but its function in pulmonary neuroendocrine cell (PNEC) differentiation has not been fully addressed. In this study, we examined the role of canonical Wnt signaling by targeting the gene for Adenomatous Polyposis Coli (Apc), which controls Wnt signaling activity via mediating phosphorylation of beta-catenin (Ctnnb). Targeting the Apc gene in lung epithelial progenitors by Nkx2.1-cre stabilized Ctnnb and activated canonical Wnt signaling. Apc deficiency altered lung epithelial cell fate by inhibiting Clara and ciliated cell differentiation and activating Uchl1, a marker of neuroendocrine cells. Similar to PNEC in normal lung, Uchl1(positive) cells were innervated. In mice with targeted inactivation of Ctnnb by Nkx2.1-cre, PNEC differentiation was not interrupted. These indicate that, after lung primordium formation, Wnt signaling is not essential for PNEC differentiation; however, its over-activation promotes PNEC features. Interestingly, Nkx2.1 was extinguished in Apc deficient epithelial progenitors before activation of Uchl1. Examination of Nkx2.1 null lungs suggested that early deletion of Nkx2.1 inhibits PNEC differentiation, while late repression does not. Nkx2.1 was specifically inhibited in Apc deficient lungs but not in Ctnnb gain-of-function lungs indicating a functional difference between Apc deletion and Ctnnb stabilization, both of which activate Wnt signaling. Further analysis revealed that Apc deficiency led to increased TGF-beta signaling, which inhibited Nkx2.1 in cultured lung endodermal explants. In contrast, TGF-beta activity was not increased in Ctnnb gain-of-function lungs. Therefore, our studies revealed an important mechanism involving Apc and TGF-beta signaling in regulating the key transcriptional factor, Nkx2.1, for lung epithelial progenitor cell fate determination.
authors.affiliation: Department of Pediatrics, USC Keck School of Medicine & Childrens Hospital Los Angeles, Los Angeles, CA 90033, USA.
authors.forename: Changgong
authors.initials: C
authors.lastname: Li
authors.forename: Aimin
authors.initials: A
authors.lastname: Li
authors.forename: Yiming
authors.initials: Y
authors.lastname: Xing
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Belinda
authors.initials: B
authors.lastname: Chan
authors.forename: Ruoyun
authors.initials: R
authors.lastname: Ouyang
authors.forename: Makoto Mark
authors.initials: MM
authors.lastname: Taketo
authors.forename: Raju
authors.initials: R
authors.lastname: Kucherlapati
authors.forename: Zea
authors.initials: Z
authors.lastname: Borok
authors.forename: Parviz
authors.initials: P
authors.lastname: Minoo
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000502:physiology*; D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D004847:Epithelial Cells / Q000166:cytology*; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D017491:Genes, APC; D008168:Lung / Q000166:cytology* / Q000196:embryology; D051379:Mice; D008954:Models, Biological; D009024:Morphogenesis; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; C000614414:Nkx2-1 protein, mouse; D009687:Nuclear Proteins; D012333:RNA, Messenger; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D016212:Transforming Growth Factor beta
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