Sox2 modulatesLef-1expression during airway submucosal gland development

Abstract

Tracheobronchial submucosal glands (SMGs) are derived from one or more multipotent glandular stem cells that coalesce to form a placode in surface airway epithelium (SAE). Wnt/β-catenin-dependent induction of lymphoid enhancer factor (Lef-1) gene expression during placode formation is an early event required for SMG morphogenesis. We discovered that Sox2 expression is repressed as Lef-1 is induced within airway SMG placodes. Deletion of Lef-1 did not activate Sox2 expression in SMG placodes, demonstrating that Lef-1 activation does not directly inhibit Sox2 expression. Repression of Sox2 protein in SMG placodes occurred posttranscriptionally, since the activity of its endogenous promoter remained unchanged in SMG placodes. Thus we hypothesized that Sox2 transcriptionally represses Lef-1 expression in the SAE and that suppression of Sox2 in SMG placodes activates Wnt/β-catenin-dependent induction of Lef-1 during SMG morphogenesis. Consistent with this hypothesis, transcriptional reporter assays, ChIP analyses, and DNA-protein binding studies revealed a functional Sox2 DNA binding site in the Lef-1 promoter that is required for suppressing β-catenin-dependent transcription. In polarized primary airway epithelium, Wnt induction enhanced Lef-1 expression while also inhibiting Sox2 expression. Conditional deletion of Sox2 also enhanced Lef-1 expression in polarized primary airway epithelium, but this induction was significantly augmented by Wnt stimulation. Our findings provide the first evidence that Sox2 acts as a repressor to directly modulate Wnt-responsive transcription of the Lef-1 gene promoter. These studies support a model whereby Wnt signals and Sox2 dynamically regulate the expression of Lef-1 in airway epithelia and potentially also during SMG development.

Ipsilateral and Contralateral Retinal Ganglion Cells Express Distinct Genes during Decussation at the Optic Chiasm

“…One highlight of our gene profiling results is that ipsilateral but not contralateral RGCs express multiple transcription factors, such as Math5 and Sox2, known to be expressed in retinal progenitor cells (Xie et al, 2014). Two possible explanations for these observations are that (1) Zic2 + RGCs are developmentally less mature than their contralateral counterparts, and failure to downregulate these genes reflect their immaturity, and (2) these progenitor cell markers have additional functions in postmitotic Zic2 + RGCs and neuronal subtype identity and function.…”

Sox2 and Lef-1 interact with Pitx2 to regulate incisor development and stem cell renewal

“…progenitor cell populations during early and late submucosal gland development (Xie et al, 2014). In tooth development, we have identified that the juxtaposed expression of Sox2 and Lef-1 in the dental placode may be coordinated by Pitx2 expression.…”

“…Sox2 has important roles in the development of several endodermal tissues, such as the trachea (Xie et al, 2014) stomach and gut (Que et al, 2007), as well as in ectodermal tissues including the anterior pituitary (Jayakody et al, 2012), lens epithelium (Taranova et al, 2006), tongue epithelium and hair follicles (Clavel et al, 2012). Sox2 was recently identified as a marker for DESCs.…”

Progenitor Cells in Proximal Airway Epithelial Development and Regeneration

“…PGPs of Lef-1knockout mice lack expression of Cyclin D1 and fail to developnormally, suggesting that Lef-1 induction in the PGP is important to drive cell cycle progression during the formation of SMGs [Driskell et al, 2007]. Canonical Wnt ligands, Wnt-1 and Wnt-3a, enhance the transcription of the Lef-1 promoter through the binding of Wnt-induced TCF/β-catenin complexes at multiple sites on the promoter [Filali, 2002; Li et al, 2006; Driskell et al, 2007; Xie et al, 2014]. More recently, studies have shown that Lef-1 transcription is modulated by Sox (SRY-related HMG box) family transcription factors, Sox2 and Soxl7, during early PGP formatio n [Liu et al, 2010; Xie et al, 2014].…”