β-Catenin Signaling Biases Multipotent Lingual Epithelial Progenitors to Differentiate and Acquire Specific Taste Cell Fates

Abstract

Continuous taste bud cell renewal is essential to maintain taste function in adults; however, the molecular mechanisms that regulate taste cell turnover are unknown. Using inducible Cre-lox technology, we show that activation of β-catenin signaling in multipotent lingual epithelial progenitors outside of taste buds diverts daughter cells from a general epithelial to a taste bud fate. Moreover, while taste buds comprise 3 morphological types, β-catenin activation drives overproduction of primarily glial-like Type I taste cells in both anterior fungiform (FF) and posterior circumvallate (CV) taste buds, with a small increase in Type II receptor cells for sweet, bitter and umami, but does not alter Type III sour detector cells. Beta-catenin activation in post-mitotic taste bud precursors likewise regulates cell differentiation; forced activation of β-catenin in these Shh+ cells promotes Type I cell fate in both FF and CV taste buds, but likely does so non-cell autonomously. Our data are consistent with a model where β-catenin signaling levels within lingual epithelial progenitors dictate cell fate prior to or during entry of new cells into taste buds; high signaling induces Type I cells, intermediate levels drive Type II cell differentiation, while low levels may drive differentiation of Type III cells.

Progress and renewal in gustation: new insights into taste bud development

“…Alternatively, if Shh marks a heterogeneous precursor population, within which fate-determining transcription factors are already differentially expressed, then extrinsic factors acting early on K5 + and/or Shh + cells will control cell fate. Recent findings support the latter hypothesis; genetic manipulation of β-catenin alters the fate of K5/14 + progenitors, whereas Shh + precursor cell fate is unaffected following cellautonomous manipulation of β-catenin (Gaillard et al, 2015).…”

“…3). Using inducible lineage tracing in adult mice, basal keratinocytes expressing cytokeratin 5 (K5, or Krt5) and K14 have been identified as the progenitor population that supplies new cells to taste buds (Gaillard et al, 2015;Okubo et al, 2009). As new cells enter the buds, they initially have an ovoid morphology and reside in the basal compartment.…”

“…3B), which makes up the majority of the tongue surface and throughout which the taste papillae are distributed (Castillo et al, 2014;Gaillard et al, 2015;Okubo et al, 2009). In contrast to taste cells, non-taste epithelial cells turn over very rapidly -within 5 days in mice (Potten et al, 2002a,b,c).…”

“…Additionally, the canonical Wnt pathway is active in adult taste buds; specifically, BATGAL reporter mice (in which β-galactosidase is expressed in the presence of nuclear β-catenin) show β-galactosidase in progenitor cells outside of buds, in Shh + taste bud precursor cells, and in subsets of each of the three taste cell types, suggesting that the pathway plays a role in each step of the taste cell lineage (Gaillard and Barlow, 2011). To assess β-catenin function, a recent study conditionally induced the overexpression (OE) of β-catenin in K5 + basal keratinocytes in adult mice (Gaillard et al, 2015). In both the anterior FFP and posterior CVP, β-catenin OE forced K5 + cells to differentiate and acquire a taste fate at the expense of K13 + non-taste epithelium (see Fig.…”

“…A similar scenario might occur for Shh and Skn1a expression during Type II cell differentiation; Skn1a is expressed by Type II cells and a subset of basal cells (Matsumoto et al, 2011), but it is unknown if Shh + cells are Skn1a + , or if Skn1a and Ascl1 are co-expressed in Shh + basal cells. Finally, despite the fact that Type I cells comprise ∼50% of taste cells (Bartel et al, 2006), there is no information on how Type I cell differentiation is regulated, other than that high β-catenin is sufficient to drive Type I fate (Gaillard et al, 2015). If Shh + precursor cells comprise a homogenous population that represents obligate intermediates for all cell types, then intrinsic transcription factors must be differentially regulated within single cells to dictate fate.…”