Foxp1/4 control epithelial cell fate during lung development and regeneration through regulation of anterior gradient 2

Abstract

SUMMARYThe molecular pathways regulating cell lineage determination and regeneration in epithelial tissues are poorly understood. The secretory epithelium of the lung is required for production of mucus to help protect the lung against environmental insults, including pathogens and pollution, that can lead to debilitating diseases such as asthma and chronic obstructive pulmonary disease. We show that the transcription factors Foxp1 and Foxp4 act cooperatively to regulate lung secretory epithelial cell fate and regeneration by directly restricting the goblet cell lineage program. Loss of Foxp1/4 in the developing lung and in postnatal secretory epithelium leads to ectopic activation of the goblet cell fate program, in part, through de-repression of the protein disulfide isomerase anterior gradient 2 (Agr2). Forced expression of Agr2 is sufficient to promote the goblet cell fate in the developing airway epithelium. Finally, in a model of lung secretory cell injury and regeneration, we show that loss of Foxp1/4 leads to catastrophic loss of airway epithelial regeneration due to default differentiation of secretory cells into the goblet cell lineage. These data demonstrate the importance of Foxp1/4 in restricting cell fate choices during development and regeneration, thereby providing the proper balance of functional epithelial lineages in the lung.

Foxp1 maintains hair follicle stem cell quiescence through regulation of Fgf18

“…The forkhead transcription factor Foxp1 regulates many different developmental processes, from spinal cord, lung and heart to B and T cell development (Wang et al, 2004;Hu et al, 2006;Shu et al, 2007;Dasen et al, 2008;Feng et al, 2010;Zhang et al, 2010;Feng et al, 2011;Li et al, 2012). In this study, we show that Foxp1 is essential for the maintenance of the quiescent state of HFSCs.…”

“…Known to act as both a transcriptional repressor and activator, Foxp1 regulates the development of many tissues, including esophagus, lung, heart, thymus and spinal cord (Wang et al, 2004;Hu et al, 2006;Shu et al, 2007;Dasen et al, 2008;Feng et al, 2010;Zhang et al, 2010;Feng et al, 2011;Li et al, 2012). Ablation of Foxp1 disrupts B cell development (Hu et al, 2006) as well as development of the lung and esophagus (Shu et al, 2007).…”

Fox transcription factors: from development to disease

“…In mammals there are four FoxP genes (Foxp1-4), and the transcription factors that they encode have been shown to play a role in the development of multiple cell types, including cardiomyocytes , neurons (Shu et al, 2005), lung epithelial secretory cells (Li et al, 2012a) and regulatory Tcells (Fontenot et al, 2003). Accordingly, FoxP null mice display varying phenotypes.…”

Small Airways in Asthma: Distal is Different

“…Recently, Foxp1 was identified as another transcriptional regulator of Agr2. Expression of Foxp1 in the murine lung acts as suppressor of GCM by repression of Agr2 [64,65]. Overwhelming ER stress caused by inappropriate regulation of mucus processing eventually leads to the induction of the stress proteins BiP and CAATenhancer-binding protein homologous protein (CHOP) [54].…”