Induction of ectopic taste buds by SHH reveals the competency and plasticity of adult lingual epithelium

Abstract

Taste buds are assemblies of elongated epithelial cells, which are innervated by gustatory nerves that transmit taste information to the brain stem. Taste cells are continuously renewed throughout life via proliferation of epithelial progenitors, but the molecular regulation of this process remains unknown. During embryogenesis, sonic hedgehog (SHH) negatively regulates taste bud patterning, such that inhibition of SHH causes the formation of more and larger taste bud primordia, including in regions of the tongue normally devoid of taste buds. Here, using a Cre-lox system to drive constitutive expression of SHH, we identify the effects of SHH on the lingual epithelium of adult mice. We show that misexpression of SHH transforms lingual epithelial cell fate, such that daughter cells of lingual epithelial progenitors form cell type-replete, onion-shaped taste buds, rather than non-taste, pseudostratified epithelium. These SHH-induced ectopic taste buds are found in regions of the adult tongue previously thought incapable of generating taste organs. The ectopic buds are composed of all taste cell types, including support cells and detectors of sweet, bitter, umami, salt and sour, and recapitulate the molecular differentiation process of endogenous taste buds. In contrast to the well-established nerve dependence of endogenous taste buds, however, ectopic taste buds form independently of both gustatory and somatosensory innervation. As innervation is required for SHH expression by endogenous taste buds, our data suggest that SHH can replace the need for innervation to drive the entire program of taste bud differentiation.

Coevolutionary patterning of teeth and taste buds

“…6, arrows). Recent study in adult mice shows that mis-expression of Shh is sufficient to induce ectopic taste placode development in lingual regions of the tongue, surprisingly independent of innervation (39). That data, in conjunction with ours, highlight differing roles of Hh and innervation in embryonic development versus adult maintenance of taste placodes (40).…”

Neuronal delivery of Hedgehog directs spatial patterning of taste organ regeneration

“…We also tested the effect of systemic SAG21k administration on normal lingual epithelium and noted the appearance of K8 + TRCs at many ectopic sites (Fig. 7F), in a manner reminiscent of that noted upon ectopic expression of Shh within the lingual epithelium in the absence of innervation (32). Because we activated the Hedgehog pathway pharmacologically, we were able to terminate ectopic pathway activation by withdrawing SAG21k, thus producing the interesting effect that nearly all ectopic TRCs degenerated within 8 wk after SAG21k withdrawal, leaving predominantly TRCs at their normal locations within the fungiform papillae (Fig.…”

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

“…Nonetheless, with respect to taste placodes, Sox2 is positively regulated by Wnt/ β-catenin and Fgf10/Spry2 signaling (Okubo et al, 2006;Petersen et al, 2011). Whether Sox2 is regulated by Shh during taste bud development is unknown, although Sox2 appears to function downstream of Shh during adult taste cell renewal (see below) (Castillo et al, 2014).…”

“…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).…”

“…In other renewing epithelia, Hedgehog (Hh) functions as a mitogen or a differentiation factor (Lee and Tumbar, 2012;Takashima and Hartenstein, 2012) or can signal to maintain stem cells (Álvarez-Buylla and Ihrie, 2014;Ferent et al, 2014;Saade et al, 2013). To examine the role of Shh in taste cell renewal, a recent study used inducible genetic models in adult mice to express Shh in K14 + lingual progenitors (Castillo et al, 2014). Unexpectedly, excess Shh caused the formation of excess and ectopic taste buds interspersed among filiform papillae of the anterior tongue; 1 month after induction, as many as 100 ectopic buds formed in the tip of the tongue, which is far more than the number of endogenous taste buds found in this region (Reiner et al, 2008).…”