Transcriptional Regulation of by Aryl Hydrocarbon Receptor: Effect on Math1 Progenitor Cells in Mouse Small Intestine.

The physiological roles of aryl hydrocarbon receptor (AhR) in the small intestine have been revealed as immunomodulatory and barrier functions. However, its contributions to cell fate regulation are incompletely understood. The Notch-activated signaling cascade is a central component of intestinal cell fate determinations. The lateral inhibitory mechanism governed by Notch directs cell fates toward distinct cell lineages (i.e., absorptive and secretory cell lineages) through its downstream effector, mouse atonal homolog 1 (MATH1). An investigation employing cell lines and intestinal crypt cells revealed that AhR regulates expression in a xenobiotic response element (XRE)-dependent manner. The AhR- axis was further addressed using intestinal organoids, where AhR- and HES1- axes appeared to coexist within the underlying transcriptional machinery. When the HES1- axis was pharmacologically suppressed, β-naphthoflavone-mediated AhR activation increased the number of goblet and Math1 progenitor cells in the organoids. The same pharmacological dissection of the AhR- axis was applied in vivo, demonstrating an enhanced number of Math1 progenitor cells in the small intestine following AhR activation. We report here that AhR- is a direct transcriptional axis with effects on Math1 progenitor cells in the small intestine, highlighting a novel molecular basis for fine-tuning Notch-mediated cell fate regulation.