Shh and Ptc are associated with taste bud maintenance in the adult mouse

Miura, Hirohito; Kusakabe, Yuko; Sugiyama, Chiaki; Kawamatsu, Michiko; Ninomiya, Yuzo; Motoyama, Jun; Hino, Akihiro

doi:10.1016/s0925-4773(01)00414-2

Cited by 95 publications

(79 citation statements)

References 10 publications

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“…2F and Fig. S3A), as also noted by others (21)(22)(23)(24). Note that the mG marking of Shh-expressing cells within the taste bud is driven by the CAG promoter inserted at the R26 locus.…”

Section: Significancesupporting

confidence: 79%

Neuronal delivery of Hedgehog directs spatial patterning of taste organ regeneration

Mann

Nguyen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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How organs maintain and restore functional integrity during ordinary tissue turnover or following injury represents a central biological problem. The maintenance of taste sensory organs in the tongue was shown 140 years ago to depend on innervation from distant ganglion neurons, but the underlying mechanism has remained unknown. Here, we show that Sonic hedgehog (Shh), which encodes a secreted protein signal, is expressed in these sensory neurons, and that experimental ablation of neuronal Shh expression causes loss of taste receptor cells (TRCs). TRCs are also lost upon pharmacologic blockade of Hedgehog pathway response, accounting for the loss of taste sensation experienced by cancer patients undergoing Hedgehog inhibitor treatment. We find that TRC regeneration following such pharmacologic ablation requires neuronal expression of Shh and can be substantially enhanced by pharmacologic activation of Hedgehog response. Such pharmacologic enhancement of Hedgehog response, however, results in additional TRC formation at many ectopic sites, unlike the site-restricted regeneration specified by the projection pattern of Shh-expressing neurons. Stable regeneration of TRCs thus requires neuronal Shh, illustrating the principle that neuronal delivery of cues such as the Shh signal can pattern distant cellular responses to assure functional integrity during tissue maintenance and regeneration.

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“…2F and Fig. S3A), as also noted by others (21)(22)(23)(24). Note that the mG marking of Shh-expressing cells within the taste bud is driven by the CAG promoter inserted at the R26 locus.…”

Section: Significancesupporting

confidence: 79%

Neuronal delivery of Hedgehog directs spatial patterning of taste organ regeneration

Mann

Nguyen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…[25][26][27] It has previously been reported that the Shh pathway is active also in the adult mouse tongue, suggesting a role in tongue epithelial/taste bud maintenance. 28 Together these findings suggest that in the adult tongue Wnt/␤-catenin is upstream of Shh and that Shh negatively regulates Wnt signaling in tongue epithelial/taste bud maintenance.…”

Section: Discussionmentioning

confidence: 87%

Sonic Hedgehog Acts as a Negative Regulator of β-Catenin Signaling in the Adult Tongue Epithelium

Schneider

Schänzer

Czupalla

et al. 2010

The American Journal of Pathology

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Wnt/␤-catenin signaling has been implicated in taste papilla development; however , its role in epithelial maintenance and tumor progression in the adult tongue remains elusive. We show Wnt/␤-catenin pathway activation in reporter mice and by nuclear ␤-catenin staining in the epithelium and taste papilla of adult mouse and human tongues. ␤-Catenin activation in APC min/؉ mice , which carry a mutation in adenomatous poliposis coli (APC), up-regulates Sonic hedgehog (Shh) and Jagged-2 (JAG2) in the tongue epithelium without formation of squamous cell carcinoma (SCC). We demonstrate that Shh suppresses ␤-catenin transcriptional activity in a signaling-dependent manner in vitro and in vivo. A similar regulation and function was observed for JAG2, suggesting that both pathways negatively regulate ␤-catenin, thereby preventing SCC formation in the tongue. This was supported by reduced nuclear ␤-catenin in the tongue epithelium of Patched ؉/؊ mice , exhibiting dominant active Shh signaling. At the invasive front of human tongue cancer , nuclear ␤-catenin and Shh were increased , suggesting their participation in tumor progression. Interestingly , Shh but not JAG2 was able to reduce ␤-catenin signaling in SCC cells , arguing for a partial loss of negative feedback on ␤-catenin transcription in tongue cancer. We show for the first time that the putative Wnt/␤-catenin targets Shh and JAG2 control ␤-catenin signaling in the adult tongue epithelium, a function that is partially lost in lingual SCC. (Am J

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“…Our double-staining experiments for BMP4-ß-gal and proliferation markers revealed that the BMP4-expressing cells in the subepithelial lamina propria are also mitotically inactive, suggesting that in concert, these epithelial and mesenchymal BMP4 cells adjacent to taste buds may maintain the niche, or signaling center for taste bud stem cells. Interestingly, Miura [32] report that Shh is expressed exclusively in basal cells within taste buds, whereas Ptch1 , a Shh receptor (reviewed by Ingham and McMahon, 2001) [75], is expressed in the epithelial cells outside of taste buds, but adjacent to intragemmal Shh expressing cells. Moreover, mitotic cells, as detected via short term BrdU incorporation are mainly in the Ptch1 expressing region, raising the likelihood that Ptch1 expressing cells comprise the transit amplifying population, and possibly the taste bud stem cells [33].…”

Section: Discussionmentioning

confidence: 99%

“…For example, Sonic hedgehog ( Shh ) is expressed in basal cells (type IV) within taste buds, while the Shh receptor, Patched1 ( Ptch1 ), is expressed in perigemmal epithelial cells adjacent to Shh -expressing cells [32,33]. Mash1 , a transcription factor in the Notch pathway, is expressed in a subset of differentiated type III cells, and is also expressed in a subset of Shh expressing basal cells, suggesting a possible function for Mash1 in the transition from basal cells to type III cells [29,34].…”

Section: Introductionmentioning

confidence: 99%

Differential expression of a BMP4 reporter allele in anterior fungiform versus posterior circumvallate taste buds of mice

Nguyen

Barlow

2010

BMC Neurosci

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BackgroundBone Morphogenetic Protein 4 (BMP4) is a diffusible factor which regulates embryonic taste organ development. However, the role of BMP4 in taste buds of adult mice is unknown. We utilized transgenic mice with LacZ under the control of the BMP4 promoter to reveal the expression of BMP4 in the tongues of adult mice. Further we evaluate the pattern of BMP4 expression with that of markers of specific taste bud cell types and cell proliferation to define and compare the cell populations expressing BMP4 in anterior (fungiform papillae) and posterior (circumvallate papilla) tongue.ResultsBMP4 is expressed in adult fungiform and circumvallate papillae, i.e., lingual structures composed of non-taste epithelium and taste buds. Unexpectedly, we find both differences and similarities with respect to expression of BMP4-driven ß-galactosidase. In circumvallate papillae, many fusiform cells within taste buds are BMP4-ß-gal positive. Further, a low percentage of BMP4-expressing cells within circumvallate taste buds is immunopositive for markers of each of the three differentiated taste cell types (I, II and III). BMP4-positive intragemmal cells also expressed a putative marker of immature taste cells, Sox2, and consistent with this finding, intragemmal cells expressed BMP4-ß-gal within 24 hours after their final mitosis, as determined by BrdU birthdating. By contrast, in fungiform papillae, BMP4-ß-gal positive cells are never encountered within taste buds. However, in both circumvallate and fungiform papillae, BMP4-ß-gal expressing cells are located in the perigemmal region, comprising basal and edge epithelial cells adjacent to taste buds proper. This region houses the proliferative cell population that gives rise to adult taste cells. However, perigemmal BMP4-ß-gal cells appear mitotically silent in both fungiform and circumvallate taste papillae, as we do not find evidence of their active proliferation using cell cycle immunomarkers and BrdU birthdating.ConclusionOur data suggest that intragemmal BMP4-ß-gal cells in circumvallate papillae are immature taste cells which eventually differentiate into each of the 3 taste cell types, whereas perigemmal BMP4-ß-gal cells in both circumvallate and fungiform papillae may be slow cycling stem cells, or belong to the stem cell niche to regulate taste cell renewal from the proliferative cell population.

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Shh and Ptc are associated with taste bud maintenance in the adult mouse

Cited by 95 publications

References 10 publications

Neuronal delivery of Hedgehog directs spatial patterning of taste organ regeneration

Neuronal delivery of Hedgehog directs spatial patterning of taste organ regeneration

Sonic Hedgehog Acts as a Negative Regulator of β-Catenin Signaling in the Adult Tongue Epithelium

Differential expression of a BMP4 reporter allele in anterior fungiform versus posterior circumvallate taste buds of mice

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