Nkx2-2 expressing taste cells in endoderm-derived taste papillae are committed to the type III lineage.

In mammals, multiple cell-signaling pathways and transcription factors regulate development of the embryonic taste system and turnover of taste cells in the adult stage. Using single-cell RNA-Seq of mouse taste cells, we found that the homeobox-containing transcription factor Nkx2-2, a target of the Sonic Hedgehog pathway and a key regulator of the development and regeneration of multiple cell types in the body, is highly expressed in type III taste cells but not in type II or taste stem cells. Using in situ hybridization and immunostaining, we confirmed that Nkx2-2 is expressed specifically in type III taste cells in the endoderm-derived circumvallate and foliate taste papillae but not in the ectoderm-derived fungiform papillae. Lineage tracing revealed that Nkx2-2-expressing cells differentiate into type III, but not type II or type I cells in circumvallate and foliate papillae. Neonatal Nkx2-2-knockout mice did not express key type III taste cell marker genes, while the expression of type II and type I taste cell marker genes were unaffected in these mice. Our findings indicate that Nkx2-2-expressing cells are committed to the type III lineage and that Nkx2-2 may be critical for the development of type III taste cells in the posterior tongue, thus illustrating a key difference in the mechanism of type III cell lineage specification between ectoderm- and endoderm-derived taste fields.

Taste buds are not derived from neural crest in mouse, chicken, and zebrafish.

Our lineage tracing studies using multiple Cre mouse lines showed a concurrent labeling of abundant taste bud cells and the underlying connective tissue with a neural crest (NC) origin, warranting a further examination on the issue of whether there is an NC derivation of taste bud cells. In this study, we mapped NC cell lineages in three different models, Sox10-iCreERT2/tdT mouse, GFP+ neural fold transplantation to GFP- chickens, and Sox10-Cre/GFP-RFP zebrafish model. We found that in mice, Sox10-iCreERT2 specifically labels NC cell lineages with a single dose of tamoxifen at E7.5 and that the labeled cells were widely distributed in the connective tissue of the tongue. No labeled cells were found in taste buds or the surrounding epithelium in the postnatal mice. In the GFP+/GFP- chicken chimera model, GFP+ cells migrated extensively to the cranial region of chicken embryos ipsilateral to the surgery side but were absent in taste buds in the base of oral cavity and palate. In zebrafish, Sox10-Cre/GFP-RFP faithfully labeled known NC-derived tissues but did not label taste buds in lower jaw or the barbel. Our data, together with previous findings in axolotl, indicate that taste buds are not derived from NC cells in rodents, birds, amphibians or teleost fish.

Increased activity of mesenchymal ALK2-BMP signaling causes posteriorly truncated microglossia and disorganization of lingual tissues.

Proper development of taste organs including the tongue and taste papillae requires interactions with the underlying mesenchyme through multiple molecular signaling pathways. The effects of bone morphogenetic proteins (BMPs) and antagonists are profound, however, the tissue-specific roles of distinct receptors are largely unknown. Here, we report that constitutive activation (ca) of ALK2-BMP signaling in the tongue mesenchyme (marked by Wnt1-Cre) caused microglossia-a dramatically smaller and misshapen tongue with a progressively severe reduction in size along the anteroposterior axis and absence of a pharyngeal region. At E10.5, the tongue primordia (branchial arches 1-4) formed in Wnt1-Cre/caAlk2 mutants while each branchial arch responded to elevated BMP signaling distinctly in gene expression of BMP targets (Id1, Snai1, Snai2, and Runx2), proliferation (Cyclin-D1) and apoptosis (p53). Moreover, elevated ALK2-BMP signaling in the mesenchyme resulted in apparent defects of lingual epithelium, muscles, and nerves. In Wnt1-Cre/caAlk2 mutants, a circumvallate papilla was missing and further development of formed fungiform papillae was arrested in late embryos. Our data collectively demonstrate that ALK2-BMP signaling in the mesenchyme plays essential roles in orchestrating various tissues for proper development of the tongue and its appendages in a region-specific manner.

Early taste buds are from Shh+ epithelial cells of tongue primordium in distinction from mature taste bud cells which arise from surrounding tissue compartments.

Mammalian taste buds emerge perinatally and most become mature 3-4 weeks after birth. Mature taste bud cells in rodents are known to be renewed by the surrounding K14+ basal epithelial cells and potentially other progenitor source(s), but the dynamics between initially developed taste buds and surrounding tissue compartments are unclear. Using the K14-Cre and Dermo1-Cre mouse lines to trace epithelial and mesenchymal cell lineages, we found that early taste buds in E18.5 and newborn mouse tongues are not derived from either lineage. At E11.5 when the tongue primordia (i.e., lingual swellings) emerge, the relatively homogeneous sonic hedgehog-expressing (Shh+) epithelial cells express Keratin (K) 8, a marker that is widely used to label taste buds. Mapping lineage of E11.0 Shh+ epithelium of the tongue rudiment with Shh-CreERT2/RFP mice demonstrated that both the early taste buds and the surrounding lingual epithelium are from the same population of progenitors - Shh+ epithelial cells of the tongue primordium. In combination with previous reports, we propose that Shh+K8+ cells in the homogeneous epithelium of tongue primordium at early embryonic stages are programmed to become taste papilla and taste bud cells. Switching off Shh and K8 expression in the Shh+ epithelial cells of the tongue primordium transforms the cells to non-gustatory cells surrounding papillae, including K14+ basal epithelial cells which will eventually contribute to the cell renewal of mature taste buds.

TrkB expression and dependence divides gustatory neurons into three subpopulations.

BACKGROUND: During development, gustatory (taste) neurons likely undergo numerous changes in morphology and expression prior to differentiation into maturity, but little is known this process or the factors that regulate it. Neuron differentiation is likely regulated by a combination of transcription and growth factors. Embryonically, most geniculate neuron development is regulated by the growth factor brain derived neurotrophic factor (BDNF). Postnatally, however, BDNF expression becomes restricted to subpopulations of taste receptor cells with specific functions. We hypothesized that during development, the receptor for BDNF, tropomyosin kinase B receptor (TrkB), may also become developmentally restricted to a subset of taste neurons and could be one factor that is differentially expressed across taste neuron subsets. METHODS: We used transgenic mouse models to label both geniculate neurons innervating the oral cavity (Phox2b+), which are primarily taste, from those projecting to the outer ear (auricular neurons) to label TrkB expressing neurons (TrkBGFP). We also compared neuron number, taste bud number, and taste receptor cell types in wild-type animals and conditional TrkB knockouts. RESULTS: Between E15.5-E17.5, TrkB receptor expression becomes restricted to half of the Phox2b + neurons. This TrkB downregulation was specific to oral cavity projecting neurons, since TrkB expression remained constant throughout development in the auricular geniculate neurons (Phox2b-). Conditional TrkB removal from oral sensory neurons (Phox2b+) reduced this population to 92% of control levels, indicating that only 8% of these neurons do not depend on TrkB for survival during development. The remaining neurons failed to innervate any remaining taste buds, 14% of which remained despite the complete loss of innervation. Finally, some types of taste receptor cells (Car4+) were more dependent on innervation than others (PLCß2+). CONCLUSIONS: Together, these findings indicate that TrkB expression and dependence divides gustatory neurons into three subpopulations: 1) neurons that always express TrkB and are TrkB-dependent during development (50%), 2) neurons dependent on TrkB during development but that downregulate TrkB expression between E15.5 and E17.5 (41%), and 3) neurons that never express or depend on TrkB (9%). These TrkB-independent neurons are likely non-gustatory, as they do not innervate taste buds.

SIS-ECM Laden with GMSC-Derived Exosomes Promote Taste Bud Regeneration.

Oral cancer has a high annual incidence rate all over the world, and the tongue is the most frequently affected anatomic structure. The current standard care is ablative surgery of malignant neoplasm, followed by tongue reconstruction with free flap. However, such reconstructive modalities with postsurgery radiotherapy or chemotherapy can hardly support the functional recovery of the tongue-particularly, functional taste bud regeneration-in reconstructed areas, thus seriously affecting patients' prognosis and life quality. Using a critical-sized tongue defect model in rats, we show that combinatory transplantation of small intestinal submucosa-extracellular matrix (SIS-ECM) with gingival mesenchymal stem cells (GMSCs) or their derivative exosomes promoted tongue lingual papillae recovery and taste bud regeneration as evidenced by increased expression of CK14, CK8, and markers for type I, II, and III taste bud cells (NTPdase 2, PLC-ß2, and AADC, respectively). In addition, our results indicate that GMSCs or their derivative exosomes could increase BDNF expression, a growth factor that plays an important role in the proliferation and differentiation of epithelial basal progenitor cells into taste bud cells. Meanwhile, we showed an elevated expression level of Shh-which is essential for development, homeostasis, and maintenance of the taste bud organ-in wounded areas of the tongue among animals treated with GMSC/SIS-ECM or exosome/SIS-ECM as compared with SIS-ECM control. Moreover, our data show that GMSCs or their derivative exosomes promoted innervation of regenerated taste buds, as evidenced by elevated expressions of neurofilament and P2X3 at the injury areas. Together, our findings indicate that GMSC/SIS-ECM and exosome/SIS-ECM constructs can facilitate taste bud regeneration and reinnervation with promising potential application in postsurgery tongue reconstruction of patients with tongue cancer.

Morphogenesis of lingual papillae of one-humped camel (Camelus dromedarius) during prenatal life: A light and scanning electron microscopic study.

This study was made on 24 camel fetuses of crown-rump vertebral length (CVRL) ranging from 10.5 cm to 105 cm CVRL (94-352 days old). These camel fetuses were classified into three groups representing the three trimesters of prenatal life. During the first trimester (94-142 days), lingual papillae (circumvallate and lentiform papillae) were demonstrated on the lingual root, but lingual body and the apex were almost free of papillae except for some scattered epithelial projections especially near the lateral borders of the body. In the second trimester (152-229 days), the lentiform papillae covered the entire root of the tongue except for areas occupied by the circumvallate papillae. Taste buds with clear pores were observed for the first time in areas between the circumvallate gustatory furrow and surface epithelium of the tongue. In addition, short numerous filiform papillae were observed on the rostral part of the lingual body and the lateral parts of the apex. Fungiform papillae, however, were demonstrated amidst the filiform papillae. In this trimester, taste buds were also seen on the top of the fungiform papillae. In the third trimester (256-352 days), all lingual papillae were clearly demonstrated on the dorsum of the root, body and apex of the tongue. Both types of gustatory papillae (circumvallate and fungiform) had well-developed taste buds. Mechanical papillae (filiform and lentiform) were well developed. Lentiform papillae occupied most of the dorsal aspect of the Torus linguae; they were larger in size with semicircular apices. Filiform papillae, however, were numerous and demonstrated heavily on the lateral and rostral parts of the body as well as on the apex of the tongue.

RNA-Seq analysis on chicken taste sensory organs: An ideal system to study organogenesis.

RNA-Seq is a powerful tool in transcriptomic profiling of cells and tissues. We recently identified many more taste buds than previously appreciated in chickens using molecular markers to stain oral epithelial sheets of the palate, base of oral cavity, and posterior tongue. In this study, RNA-Seq was performed to understand the transcriptomic architecture of chicken gustatory tissues. Interestingly, taste sensation related genes and many more differentially expressed genes (DEGs) were found between the epithelium and mesenchyme in the base of oral cavity as compared to the palate and posterior tongue. Further RNA-Seq using specifically defined tissues of the base of oral cavity demonstrated that DEGs between gustatory (GE) and non-gustatory epithelium (NGE), and between GE and the underlying mesenchyme (GM) were enriched in multiple GO terms and KEGG pathways, including many biological processes. Well-known genes for taste sensation were highly expressed in the GE. Moreover, genes of signaling components important in organogenesis (Wnt, TGFß/ BMP, FGF, Notch, SHH, Erbb) were differentially expressed between GE and GM. Combined with other features of chicken taste buds, e.g., uniquely patterned array and short turnover cycle, our data suggest that chicken gustatory tissue provides an ideal system for multidisciplinary studies, including organogenesis and regenerative medicine.

Ultrastructure of Lingual Papillae in Common Chimpanzee (Pan troglodytes) Foetus, Newborn and Adult Specimens.

Among primates, the two recognized species of chimpanzees (common chimpanzee, Pan troglodytes; pygmy chimpanzee, Pan paniscus) are considered to be the most similar to humans. Importantly, in mammals, the food intake behaviour largely determines the tongue morphology, including the type, proportion and distribution of gustatory and non-gustatory tongue papillae. The lingual papillae form during its development and mature in post-natal life depending on the different feeding. In this study, we have used scanning electron microscopy to analyse the age-related changes in the lingual papillae of foetal, newborn and adult P. troglodytes. Four main types of lingual papillae, denominated filiform, fungiform, foliate and vallate, and one subtype of filiform papillae called conical papillae, were found. The main age-related changes observed in all kinds of papillae were a progressive keratinization and morphological complexity along the lifespan. During the foetal period, there was scarce keratinization, which progressively increases in young animals to adulthood. The number of filiform increased with ageing, and both filiform and fungiform papillae in adult tongues are divided into pseudopapillae. On the other hand, the vallate papillae vary from smooth simple surfaces in foetal tongues to irregular surfaces with grooves and pseudopapillae (microscopic papilla-shaped formations within the papilla itself) in adults. These results describe for the first time the age-related variations in the three-dimensional aspect of lingual papillae of the chimpanzee tongue and provide new data to characterize more precisely these structures in the human closest specie.

FGF signaling refines Wnt gradients to regulate the patterning of taste papillae.

The patterning of repeated structures is a major theme in developmental biology, and the inter-relationship between spacing and size of such structures is an unresolved issue. Fungiform papillae are repeated epithelial structures that house taste buds on the anterior tongue. Here, we report that FGF signaling is a crucial regulator of fungiform papillae development. We found that mesenchymal FGF10 controls the size of the papillary area, while overall patterning remains unchanged. Our results show that FGF signaling negatively affects the extent of canonical Wnt signaling, which is the main activation pathway during fungiform papillae development; however, this effect does not occur at the level of gene transcription. Rather, our experimental data, together with computational modeling, indicate that FGF10 modulates the range of Wnt effects, likely via induction of Sostdc1 expression. We suggest that modification of the reach of Wnt signaling could be due to local changes in morphogen diffusion, representing a novel mechanism in this tissue context, and we propose that this phenomenon might be involved in a broader array of mammalian developmental processes.

Grhl3 modulates epithelial structure formation of the circumvallate papilla during mouse development.

Grainyhead-like 3 (Grhl3) is a transcription factor involved in epithelial morphogenesis. In the present study, we evaluated the developmental role of Grhl3 in structural formation of the circumvallate papilla (CVP), which undergoes dynamic morphological changes during organogenesis. The specific expression pattern of Grhl3 was examined in the CVP-forming region, specifically in the apex and epithelial stalk from E13.5 to E15.5 using in situ hybridization. To determine the role of Grhl3 in epithelial morphogenesis of the CVP, we employed an in vitro tongue culture method, wherein E13.5 tongue were isolated and cultured for 2 days after knocking down of Grhl3. Knockdown of Grhl3 resulted in significant changes to the epithelial structure of the CVP, such that the apical region of the CVP was smaller in size, and the epithelial stalks were more deeply invaginated. To define the mechanisms underlying these morphological alterations, we examined cell migration, proliferation, and apoptosis using phalloidin staining, immunohistochemistry against Ki67, ROCK1, and E-cadherin, and a TUNEL assay, respectively. These results revealed an increase in proliferation, a reduction in apoptosis, and an altered pattern of cytoskeletal formation in the CVP-forming epithelium, following Grhl3 knockdown. In addition, there were changes in the specific expression patterns of signaling and apoptosis-related molecules such as Axin2, Bak1, Bcl2, Casp3, Casp8, Ctnnb1, Cnnd1, Gli3, Lef1, Ptch1, Rock1, Shh, and Wnt11, which could explain the altered cellular and morphological events. Based on these results, we propose that developmental stage-specific Grhl3 plays a significant role in CVP morphogenesis not by just disruption of epithelial integrity but by regulating epithelial cell proliferation, apoptosis, and migration via Shh, Wnt, and apoptosis signaling during mouse embryogenesis.

Distribution of α-Gustducin and Vimentin in premature and mature taste buds in chickens.

The sensory organs for taste in chickens (Gallus sp.) are taste buds in the oral epithelium of the palate, base of the oral cavity, and posterior tongue. Although there is not a pan-taste cell marker that labels all chicken taste bud cells, α-Gustducin and Vimentin each label a subpopulation of taste bud cells. In the present study, we used both α-Gustducin and Vimentin to further characterize chicken taste buds at the embryonic and post-hatching stages (E17-P5). We found that both α-Gustducin and Vimentin label distinct and overlapping populations of, but not all, taste bud cells. A-Gustducin immunosignals were observed as early as E18 and were consistently distributed in early and mature taste buds in embryos and hatchlings. Vimentin immunoreactivity was initially sparse at the embryonic stages then became apparent in taste buds after hatch. In hatchlings, α-Gustducin and Vimentin immunosignals largely co-localized in taste buds. A small subset of taste bud cells were labeled by either α-Gustducin or Vimentin or were not labeled. Importantly, each of the markers was observed in all of the examined taste buds. Our data suggest that the early onset of α-Gustducin in taste buds might be important for enabling chickens to respond to taste stimuli immediately after hatch and that distinctive population of taste bud cells that are labeled by different molecular markers might represent different cell types or different phases of taste bud cells. Additionally, α-Gustducin and Vimentin can potentially be used as molecular markers of all chicken taste buds in whole mount tissue.

Nerve-independent and ectopically additional induction of taste buds in organ culture of fetal tongues.

An improved organ culture system allowed to observe morphogenesis of mouse lingual papillae and taste buds relatively for longer period, in which fetal tongues were analyzed for 6 d. Taste cells were defined as eosinophobic epithelial cells expressing CK8 and Sox2 within lingual epithelium. Addition of glycogen synthase kinase 3 beta inhibitor CHIR99021 induced many taste cells and buds in non-gustatory and gustatory stratified lingual epithelium. The present study clearly demonstrated induction of taste cells and buds ectopically and without innervation.

Bcl11b/Ctip2 is required for development of lingual papillae in mice.

Molecular mechanisms underlying the development and morphogenesis of oral epithelia, comprising the gustatory and nongustatory epithelium, remain unclear. Here, we show that Bcl11b, a zinc finger transcription factor, plays an important role in the development of lingual papillae, especially filiform papillae. In both gustatory and nongustatory epithelium, Bcl11b was expressed in keratin 14-positive epithelial basal cells, which differentiate into keratinocytes and/or taste cells. Loss of Bcl11b function resulted in abnormal morphology of the gustatory papillae: flattened fungiform papillae, shorter trench wall in the foliate and circumvallate papillae, and ectopic invagination in more than half of circumvallate papillae. However, Bcl11b loss caused no effect on differentiation of taste receptor cells. In nongustatory epithelium, the impact of Bcl11b deficiency was much more striking, resulting in a smooth surface on the tongue tip and hypoplastic filiform papillae in the dorsal lingual epithelium. Immunohistochemical analyses revealed that a keratinocyte differentiation marker, Tchh expression was severely decreased in the Bcl11b(-/-) filiform papillae. In addition, expression of Pax9, required for morphogenesis of filiform papillae and its downstream target genes, hard keratins, almost disappeared in the tongue tip and was decreased in the dorsal tongue of Bcl11b(-/-) mice. Gene expression analyses demonstrated a delayed onset of expression of epithelial differentiation complex genes, which disturbed barrier formation in the mutant tongue. These results indicate that Bcl11b regulates the differentiation of keratinocytes in the tongue and identify Bcl11b as an essential factor for the lingual papilla morphogenesis.

LGN plays distinct roles in oral epithelial stratification, filiform papilla morphogenesis and hair follicle development.

Oral epithelia protect against constant challenges by bacteria, viruses, toxins and injury while also contributing to the formation of ectodermal appendages such as teeth, salivary glands and lingual papillae. Despite increasing evidence that differentiation pathway genes are frequently mutated in oral cancers, comparatively little is known about the mechanisms that regulate normal oral epithelial development. Here, we characterize oral epithelial stratification and describe multiple distinct functions for the mitotic spindle orientation gene LGN (Gpsm2) in promoting differentiation and tissue patterning in the mouse oral cavity. Similar to its function in epidermis, apically localized LGN directs perpendicular divisions that promote stratification of the palatal, buccogingival and ventral tongue epithelia. Surprisingly, however, in dorsal tongue LGN is predominantly localized basally, circumferentially or bilaterally and promotes planar divisions. Loss of LGN disrupts the organization and morphogenesis of filiform papillae but appears to be dispensable for embryonic hair follicle development. Thus, LGN has crucial tissue-specific functions in patterning surface ectoderm and its appendages by controlling division orientation.

Tongue and taste organ development in the ontogeny of direct-developing salamander Plethodon cinereus (Lissamphibia: Plethodontidae).

The latest research on direct developing caecilian and anuran species indicate presence of only one generation of taste organs during their ontogeny. This is distinct from indirect developing batrachians studied thus far, which possess taste buds in larvae and anatomically distinct taste discs in metamorphs. This study is a description of the tongue and taste organ morphology and development in direct developing salamander Plethodon cinereus (Plethodontidae) using histology and electron microscopy techniques. The results reveal two distinct stages tongue morphology (primary and secondary), similar to metamorphic urodeles, although only one stage of taste organ morphology. Taste disc sensory zones emerge on the surface of the oropharyngeal epithelium by the end of embryonic development, which coincides with maturation of the soft tongue. Taste organs occur in the epithelium of the tongue pad (where they are situated on the dermal papillae), the palate and the inner surface of the mandible and the maxilla. Plethodon cinereus embryos only possess taste disc type taste organs. Similar to the direct developing anuran Eleutherodactylus coqui (Eleutherodactylidae), these salamanders do not recapitulate larval taste bud morphology as an embryo. The lack of taste bud formation is probably a broadly distributed feature characteristic to direct developing batrachians. J. Morphol. 277:906-915, 2016. © 2016 Wiley Periodicals, Inc.

Ontogeny and innervation of taste buds in mouse palatal gustatory epithelium.

We investigated the relationship between mouse taste bud development and innervation of the soft palate. We employed scanning electron microscopy and immunohistochemistry using antibodies against protein gene product 9.5 and peripherin to detect sensory nerves, and cytokeratin 8 and α-gustducin to stain palatal taste buds. At E14, nerve fibers were observed along the medial border of the palatal shelves that tracked toward the epithelium. At E15.5, primordial stages of taste buds in the basal lamina of the soft palate first appeared. At E16, the taste buds became large spherical masses of columnar cells scattered in the soft palate basal lamina. At E17, the morphology and also the location of taste buds changed. At E18-19, some taste buds acquired a more elongated shape with a short neck, extending a variable distance from the soft palate basal lamina toward the surface epithelium. At E18, mature taste buds with taste pores and perigemmal nerve fibers were observed on the surface epithelium of the soft palate. The expression of α-gustducin was demonstrated at postnatal day 1 and the number of pored taste buds increased with age and they became pear-shaped at 8 weeks. The percent of pored fungiform-like papillae at birth was 58.3% of the whole palate; this increased to 83.8% at postnatal day 8 and reached a maximum of 95.7% at 12 weeks. The innervation of the soft palate was classified into three types of plexuses in relation to taste buds: basal nerve plexus, intragemmal and perigemmal nerve fibers. This study reveals that the nerve fibers preceded the development of taste buds in the palate of mice, and therefore the nerve fibers have roles in the initial induction of taste buds in the soft palate.

Developmental Plasticity of Patterned and Regenerating Oral Organs.

In many aquatic vertebrates, including bony and cartilaginous fishes, teeth and taste buds colocalize on jaw elements. In these animals, taste buds are renewed continuously throughout life, whereas teeth undergo cycled whole-organ replacement by various means. Recently, studies of cichlid fishes have yielded new insights into the development and regeneration of these dental and sensory oral organs. Tooth and taste bud densities covary positively across species with different feeding strategies, controlled by common regions of the genome and integrated molecular signals. Developing teeth and taste buds share a bipotent epithelium during early patterning stages, from which dental and taste fields are specified. Moreover, these organs share a common epithelial ribbon that supports label-retaining cells during later stages of regeneration. During both patterning and regeneration stages, dental organs can be converted to taste bud fate by manipulation of BMP signaling. These observations highlight a surprising long-term plasticity between dental and sensory organ types. Here, we review these findings and discuss the implications of developmental plasticity that spans the continuum of craniofacial organ patterning and regeneration.

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

The sense of taste, or gustation, is mediated by taste buds, which are housed in specialized taste papillae found in a stereotyped pattern on the surface of the tongue. Each bud, regardless of its location, is a collection of ∼100 cells that belong to at least five different functional classes, which transduce sweet, bitter, salt, sour and umami (the taste of glutamate) signals. Taste receptor cells harbor functional similarities to neurons but, like epithelial cells, are rapidly and continuously renewed throughout adult life. Here, I review recent advances in our understanding of how the pattern of taste buds is established in embryos and discuss the cellular and molecular mechanisms governing taste cell turnover. I also highlight how these findings aid our understanding of how and why many cancer therapies result in taste dysfunction.

Coevolutionary patterning of teeth and taste buds.

Teeth and taste buds are iteratively patterned structures that line the oro-pharynx of vertebrates. Biologists do not fully understand how teeth and taste buds develop from undifferentiated epithelium or how variation in organ density is regulated. These organs are typically studied independently because of their separate anatomical location in mammals: teeth on the jaw margin and taste buds on the tongue. However, in many aquatic animals like bony fishes, teeth and taste buds are colocalized one next to the other. Using genetic mapping in cichlid fishes, we identified shared loci controlling a positive correlation between tooth and taste bud densities. Genome intervals contained candidate genes expressed in tooth and taste bud fields. sfrp5 and bmper, notable for roles in Wingless (Wnt) and bone morphogenetic protein (BMP) signaling, were differentially expressed across cichlid species with divergent tooth and taste bud density, and were expressed in the development of both organs in mice. Synexpression analysis and chemical manipulation of Wnt, BMP, and Hedgehog (Hh) pathways suggest that a common cichlid oral lamina is competent to form teeth or taste buds. Wnt signaling couples tooth and taste bud density and BMP and Hh mediate distinct organ identity. Synthesizing data from fish and mouse, we suggest that the Wnt-BMP-Hh regulatory hierarchy that configures teeth and taste buds on mammalian jaws and tongues may be an evolutionary remnant inherited from ancestors wherein these organs were copatterned from common epithelium.