Anterior and Posterior Tongue Regions and Taste Papillae: Distinct Roles and Regulatory Mechanisms with an Emphasis on Hedgehog Signaling and Antagonism

Abstract

Sensory receptors across the entire tongue are engaged during eating. However, the tongue has distinctive regions with taste (fungiform and circumvallate) and non-taste (filiform) organs that are composed of specialized epithelia, connective tissues, and innervation. The tissue regions and papillae are adapted in form and function for taste and somatosensation associated with eating. It follows that homeostasis and regeneration of distinctive papillae and taste buds with particular functional roles require tailored molecular pathways. Nonetheless, in the chemosensory field, generalizations are often made between mechanisms that regulate anterior tongue fungiform and posterior circumvallate taste papillae, without a clear distinction that highlights the singular taste cell types and receptors in the papillae. We compare and contrast signaling regulation in the tongue and emphasize the Hedgehog pathway and antagonists as prime examples of signaling differences in anterior and posterior taste and non-taste papillae. Only with more attention to the roles and regulatory signals for different taste cells in distinct tongue regions can optimal treatments for taste dysfunctions be designed. In summary, if tissues are studied from one tongue region only, with associated specialized gustatory and non-gustatory organs, an incomplete and potentially misleading picture will emerge of how lingual sensory systems are involved in eating and altered in disease.

Keywords: Hedgehog antagonism; Hedgehog signaling; chorda tympani nerve; circumvallate papilla; fungiform papilla; glossopharyngeal nerve; sonidegib; taste; taste bud; taste bud progenitors.

Figure 1

Anterior and posterior tongue papillae and nerves: Diagram of the tongue dorsum illustrating the taste organs, multiple fungiform (rounded) and single circumvallate (U-shaped) papillae on the anterior and posterior tongue, respectively. Minor salivary von Ebner glands, associated with circumvallate papillae, are labelled in the posterior tongue. The gustatory nerves, chorda tympani (yellow) and glossopharyngeal (blue), project from the corresponding sensory ganglia, geniculate and petrosal, respectively, to the anterior and posterior papilla taste buds. The somatosensory lingual nerve (green) fibers derive from the trigeminal ganglion, enter the anterior tongue together with the chorda tympani, and are within the connective tissue core of the Fungiform and non-gustatory Filiform papillae. The central projections of these nerves from the ganglia are represented in dashed lines. Hypoglossal and vagus motor fibers innervate the extrinsic and intrinsic tongue muscles and the posterior palatoglossus muscles. The boxed diagrams are as follows: The fungiform papilla, surrounded by non-taste filiform papillae, includes a single apical taste bud and a broad connective tissue core with stromal cells and innervation. The circumvallate papilla has numerous taste buds aligned next to each other in the epithelium with innervation and stromal cells in the connective tissues. The legend includes taste bud cell types (Type I, II, and III), taste bud progenitors (Type IV basal cells, perigemmal cells, and basal epithelial cells), and elements of the connective tissue core.

Figure 2

Taste bud (TB) progenitors. Different TB progenitor populations are demonstrated in the fungiform and circumvallate papillae: Type IV basal cells are within the TB; perigemmal cells are positioned outside of the TB; basal epithelial cells line the entire basement membrane of the papillae and are more locally positioned in the circumvallate papilla as compared to long-distance cells in the fungiform papilla wall.

Figure 3

SHH expression in lingual papilla taste buds, nerves, and ganglia. (A–D’). RFP (red) expression after 30 days of tamoxifen administration in Shh^CreER;R26^RFP mice. (A,B). In both the anterior tongue fungiform (A) and posterior circumvallate (B) papillae, taste buds include Shh+ cells and their progeny (green oval outlines), while the connective tissue core includes Shh+ nerve fibers (white arrows). (C–D’). Chorda tympani nerve fibers ((C), P2X3+, green) and cell bodies in the geniculate ganglion (C’) are Shh+. Although all lingual nerve fibers ((D), NF+, green) do not express Shh, cell bodies in the trigeminal ganglion (D’) are Shh+. White dotted lines demarcate the basal lamina in subfigures (A–D). Yellow dotted line marks the apical taste buds regions in the papilla cleft in subfigure (B). Scale bar: 50 μm, applies to all images.

Figure 4

Hedgehog signaling components in anterior and posterior tongue papillae. (A–F). X-Gal staining (blue) for Ptch1^lacZ (A,B), Gli1^lacZ (C,D), and Gli2^lacZ (E,F) mice in taste fungiform (A,C,E) and circumvallate (B,D,F) papillae. Ptch1 and Gli1 are expressed in papilla basal epithelial, perigemmal, and stromal cells, while Gli2 is additionally present in anterior tongue non-taste, filiform basal epithelial and stromal cells. Black dotted lines in (A,C,E) demarcate the basal lamina. Scale bar (50 μm) in (A) applies to (A,C,E) and in (B) applies to (B,D,F).

Figure 5

Paracrine SHH signaling in taste papillae epithelium and stroma. SHH ligand is present in Type IV basal cells and signals to Gli1+ and Ptch1+ HH-responding cells in the anterior tongue fungiform and posterior circumvallate papilla epithelium and stroma. Black arrows indicate epithelial paracrine signaling, and red arrows indicate neural paracrine signaling. In the fungiform papilla, epithelial SHH drives signaling in basal cells, perigemmal cells, and stromal cells (black arrows), while neural SHH signals to stromal cells (red arrow) (Note that neural paracrine signaling within the taste bud also has been suggested [108]). On the other hand, in the circumvallate papilla, epithelial SHH-responding targets are predominantly basal and perigemmal cells (black arrows), while neural SHH can target both basal and stromal cells (red arrows).

Figure 6

HH antagonist HHIP expression in fungiform and circumvallate papillae. (A–D) Antibody detection of endogenous HHIP (red) after vehicle (A,C) and sonidegib (B,D) treatment. (A,B) In the anterior tongue papillae, HHIP is expressed in the non-taste filiform papilla (white arrow) but not in the fungiform papilla or within the taste bud (green, K8) (A). After HH pathway inhibition with sonidegib, HHIP is ectopically expressed at the fungiform papilla apex (white arrowhead) (B). (C,D) In the circumvallate papilla there is no HHIP expression in the vehicle tongue (C). Unlike the fungiform papilla, ectopic HHIP is not observed after sonidegib exposure (D). White dotted lines demarcate basal lamina and yellow dotted lines mark the tongue surface in subfigures (A,B). White dotted lines in subfigures (C,D) outline the circumvallate papilla walls. Scale bar (50 μm) in (A) applies to (A,B) and (C) applies to (C,D).