scholarly journals Hedgehog Signaling Regulates Taste Organs and Oral Sensation: Distinctive Roles in the Epithelium, Stroma, and Innervation

2019 ◽  
Vol 20 (6) ◽  
pp. 1341 ◽  
Author(s):  
Charlotte Mistretta ◽  
Archana Kumari
Keyword(s):  
Hedgehog Signaling ◽  
Nerve Fibers ◽  
Taste Buds ◽  
Drug Discontinuation ◽  
Taste Sensation ◽  
Lingual Epithelium ◽  
Basic Biology ◽  
Hh Signaling ◽  
Ganglion Neurons ◽  
Tissue Compartments

The Hedgehog (Hh) pathway has regulatory roles in maintaining and restoring lingual taste organs, the papillae and taste buds, and taste sensation. Taste buds and taste nerve responses are eliminated if Hh signaling is genetically suppressed or pharmacologically inhibited, but regeneration can occur if signaling is reactivated within the lingual epithelium. Whereas Hh pathway disruption alters taste sensation, tactile and cold responses remain intact, indicating that Hh signaling is modality-specific in regulation of tongue sensation. However, although Hh regulation is essential in taste, the basic biology of pathway controls is not fully understood. With recent demonstrations that sonic hedgehog (Shh) is within both taste buds and the innervating ganglion neurons/nerve fibers, it is compelling to consider Hh signaling throughout the tongue and taste organ cell and tissue compartments. Distinctive signaling centers and niches are reviewed in taste papilla epithelium, taste buds, basal lamina, fibroblasts and lamellipodia, lingual nerves, and sensory ganglia. Several new roles for the innervation in lingual Hh signaling are proposed. Hh signaling within the lingual epithelium and an intact innervation each is necessary, but only together are sufficient to sustain and restore taste buds. Importantly, patients who use Hh pathway inhibiting drugs confront an altered chemosensory world with loss of taste buds and taste responses, intact lingual touch and cold sensation, and taste recovery after drug discontinuation.

scholarly journals SOX2 Regulation by Hedgehog Signaling Controls Adult Lingual Epithelium Homeostasis

2018 ◽  
Author(s):  
David Castillo-Azofeifa ◽  
Kerstin Seidel ◽  
Lauren Gross ◽  
Belkis Jacquez ◽  
Ophir D. Klein ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Hedgehog Signaling ◽  
Taste Buds ◽  
Taste Bud ◽  
Lingual Epithelium ◽  
Sox2 Expression ◽  
Dividing Cells ◽  
Constitutive Overexpression ◽  
Hh Signaling ◽  
Epithelial Layers

AbstractThe adult tongue epithelium is continuously renewed from epithelial progenitor cells, and this process relies on intact Hedgehog (HH) signaling. In mice, inhibition of the HH pathway using Smoothened antagonists (HH pathway inhibitors or HPIs) leads to taste bud loss over a span of several weeks. Previously, we demonstrated that overexpression of Sonic Hedgehog (SHH) in lingual epithelial progenitors induces formation of ectopic taste buds accompanied by locally increased SOX2 expression, consistent with the hypothesis that taste bud differentiation depends on SOX2 downstream of HH. To test this idea, we inhibited HH signaling by treating SOX2-GFP mice with HPI and found a rapid and drastic decline in SOX2-GFP expression in taste progenitors and taste buds. Using a conditional Cre-lox system to delete Sox2, we found that loss of SOX2 blocks differentiation of both taste buds and non-taste epithelium that comprises the majority of the tongue surface; progenitor cells increase in number at the expense of differentiated taste cells and lingual keratinocytes. In contrast to the normal pattern of basally restricted proliferation, dividing cells are overabundant, disorganized and present in suprabasal epithelial layers in Sox2 deleted tongues. Additionally, SOX2 loss in taste progenitors leads non-cell autonomously to rapid loss of taste bud cells via apoptosis, dramatically shortening taste cell lifespans. Finally, when Sox2 is conditionally deleted in mice with constitutive overexpression of SHH, ectopic taste buds fail to form and endogenous taste buds disappear; instead, robust hyperproliferation takes over the entire lingual epithelium. In sum, our experiments suggest that SOX2 functions downstream of HH signaling to regulate lingual epithelium homeostasis.

scholarly journals Hedgehog pathway blockade with the cancer drug LDE225 disrupts taste organs and taste sensation

2015 ◽  
Vol 113 (3) ◽  
pp. 1034-1040 ◽  
Author(s):  
Archana Kumari ◽  
Alexandre N. Ermilov ◽  
Benjamin L. Allen ◽  
Robert M. Bradley ◽  
Andrzej A. Dlugosz ◽  
...  
Keyword(s):  
Basal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Basal Cell ◽  
Taste Buds ◽  
Taste Bud ◽  
Chorda Tympani ◽  
Taste Sensation ◽  
Chorda Tympani Nerve ◽  
Receptor Cells ◽  
Hh Signaling

Taste sensation on the anterior tongue requires chorda tympani nerve function and connections with continuously renewing taste receptor cells. However, it is unclear which signaling pathways regulate the receptor cells to maintain chorda tympani sensation. Hedgehog (HH) signaling controls cell proliferation and differentiation in numerous tissues and is active in taste papillae and taste buds. In contrast, uncontrolled HH signaling drives tumorigenesis, including the common skin cancer, basal cell carcinoma. Systemic HH pathway inhibitors (HPIs) lead to basal cell carcinoma regression, but these drugs cause severe taste disturbances. We tested the hypothesis that taste disruption by HPIs reflects a direct requirement for HH signaling in maintaining taste organs and gustatory sensation. In mice treated with the HPI LDE225 up to 28 days, HH-responding cells were lost in fungiform papilla epithelium, and papillae acquired a conical apex. Taste buds were either absent or severely reduced in size in more than 90% of aberrant papillae. Taste bud remnants expressed the taste cell marker keratin 8, and papillae retained expression of nerve markers, neurofilament and P2X3. Chorda tympani nerve responses to taste stimuli were markedly reduced or absent in LDE225-treated mice. Responses to touch were retained, however, whereas cold responses were retained after 16 days of treatment but lost after 28 days. These data identify a critical, modality-specific requirement for HH signaling in maintaining taste papillae, taste buds and neurophysiological taste function, supporting the proposition that taste disturbances in HPI-treated patients are an on-target response to HH pathway blockade in taste organs.

scholarly journals Vismodegib, an antagonist of hedgehog signaling, directly alters taste molecular signaling in taste buds

2014 ◽  
Vol 4 (2) ◽  
pp. 245-252 ◽  
Author(s):  
Hyekyung Yang ◽  
Wei‐na Cong ◽  
Jeong Seon Yoon ◽  
Josephine M. Egan
Keyword(s):  
Hedgehog Signaling ◽  
Taste Buds ◽  
Molecular Signaling

scholarly journals Gene-teratogen interactions influence the penetrance of birth defects by altering Hedgehog signaling strength

Development ◽  
2021 ◽  
Vol 148 (19) ◽  
Author(s):  
Jennifer H. Kong ◽  
Cullen B. Young ◽  
Ganesh V. Pusapati ◽  
F. Hernán Espinoza ◽  
Chandni B. Patel ◽  
...  
Keyword(s):  
Small Molecules ◽  
Birth Defects ◽  
Birth Defect ◽  
Hedgehog Signaling ◽  
Multiple Birth ◽  
In Utero Exposure ◽  
Membrane Protein Complex ◽  
Protein Target ◽  
Hh Signaling ◽  
Genetic And Environmental Factors

ABSTRACT Birth defects result from interactions between genetic and environmental factors, but the mechanisms remain poorly understood. We find that mutations and teratogens interact in predictable ways to cause birth defects by changing target cell sensitivity to Hedgehog (Hh) ligands. These interactions converge on a membrane protein complex, the MMM complex, that promotes degradation of the Hh transducer Smoothened (SMO). Deficiency of the MMM component MOSMO results in elevated SMO and increased Hh signaling, causing multiple birth defects. In utero exposure to a teratogen that directly inhibits SMO reduces the penetrance and expressivity of birth defects in Mosmo−/− embryos. Additionally, tissues that develop normally in Mosmo−/− embryos are refractory to the teratogen. Thus, changes in the abundance of the protein target of a teratogen can change birth defect outcomes by quantitative shifts in Hh signaling. Consequently, small molecules that re-calibrate signaling strength could be harnessed to rescue structural birth defects.

scholarly journals Osteocalcin expressing cells from tendon sheaths in mice contribute to tendon repair by activating Hedgehog signaling

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Yi Wang ◽  
Xu Zhang ◽  
Huihui Huang ◽  
Yin Xia ◽  
YiFei Yao ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Hedgehog Signaling ◽  
Progenitor Cell ◽  
Tendon Repair ◽  
Tendon Sheath ◽  
Lineage Tracing ◽  
Specific Marker ◽  
Molecular Function ◽  
Hh Signaling ◽  
Necessary And Sufficient

Both extrinsic and intrinsic tissues contribute to tendon repair, but the origin and molecular functions of extrinsic tissues in tendon repair are not fully understood. Here we show that tendon sheath cells harbor stem/progenitor cell properties and contribute to tendon repair by activating Hedgehog signaling. We found that Osteocalcin (Bglap) can be used as an adult tendon-sheath-specific marker in mice. Lineage tracing experiments show that Bglap-expressing cells in adult sheath tissues possess clonogenic and multipotent properties comparable to those of stem/progenitor cells isolated from tendon fibers. Transplantation of sheath tissues improves tendon repair. Mechanistically, Hh signaling in sheath tissues is necessary and sufficient to promote the proliferation of Mkx-expressing cells in sheath tissues, and its action is mediated through TGFβ/Smad3 signaling. Furthermore, co-localization of GLI1+ and MKX+ cells is also found in human tendinopathy specimens. Our work reveals the molecular function of Hh signaling in extrinsic sheath tissues for tendon repair.

Role of knot (kn) in Wing Patterning in Drosophila

Genetics ◽  
1997 ◽  
Vol 147 (3) ◽  
pp. 1203-1212 ◽  
Author(s):  
Katerina Nestoras ◽  
Helena Lee ◽  
Jym Mohler
Keyword(s):  
Hedgehog Signaling ◽  
Imaginal Disc ◽  
Hedgehog Signaling Pathway ◽  
Posterior Compartment ◽  
Drosophila Wing ◽  
Compartment Boundary ◽  
Hh Signaling ◽  
Embryonic Segmentation ◽  
Anterior Posterior

We have undertaken a genetic analysis of new strong alleles of knot (kn). The original kn1 mutation causes an alteration of wing patterning similar to that associated with mutations of fused (fu), an apparent fusion of veins 3 and 4 in the wing. However, unlike fu, strong kn mutations do not affect embryonic segmentation and indicate that kn is not a component of a general Hh (Hedgehog)-signaling pathway. Instead we find that kn has a specific role in those cells of the wing imaginal disc that are subject to ptc-mediated Hh-signaling. Our results suggest a model for patterning the medial portion of the Drosophila wing, whereby the separation of veins 3 and 4 is maintained by kn activation in the intervening region in response to Hh-signaling across the adjacent anterior-posterior compartment boundary.

Taste buds develop autonomously from endoderm without induction by cephalic neural crest or paraxial mesoderm

Development ◽  
1997 ◽  
Vol 124 (5) ◽  
pp. 949-957 ◽  
Author(s):  
L.A. Barlow ◽  
R.G. Northcutt
Keyword(s):  
Epithelial Cells ◽  
Neural Crest ◽  
Explant Culture ◽  
Nerve Fibers ◽  
Taste Buds ◽  
Paraxial Mesoderm ◽  
Culture Techniques ◽  
Well Differentiated ◽  
Neural Crest Migration

Although it had long been believed that embryonic taste buds in vertebrates were induced to differentiate by ingrowing nerve fibers, we and others have recently shown that embryonic taste buds can develop normally in the complete absence of innervation. This leads to the question of which tissues, if any, induce the formation of taste buds in oropharyngeal endoderm. We proposed that taste buds, like many specialized epithelial cells, might arise via an inductive interaction between the endodermal epithelial cells that line the oropharynx and the adjacent mesenchyme that is derived from both cephalic neural crest and paraxial mesoderm. Using complementary grafting and explant culture techniques, however, we have now found that well-differentiated taste buds will develop in tissue completely devoid of neural crest and paraxial mesoderm derivatives. When the presumptive oropharyngeal region was removed from salamander embryos prior to the onset of cephalic neural crest migration, taste buds developed in grafts and explants coincident with their appearance in intact control embryos. Similarly, explants from neurulae in which movement of paraxial mesoderm had not yet begun also developed taste buds after 9–12 days in vitro. We conclude that neither cranial neural crest nor paraxial mesoderm is responsible for the induction of embryonic taste buds. Surprisingly, the ability to develop taste buds late in embryonic development seems to be an intrinsic feature of the oropharyngeal endoderm that is determined by the completion of gastrulation.

The relation of taste buds to their nerve fibers

1934 ◽  
Vol 59 (2) ◽  
pp. 203-220 ◽  
Author(s):  
Theodore W. Torrey
Keyword(s):  
Nerve Fibers ◽  
Taste Buds

scholarly journals Ectopic Hedgehog Signaling Causes Cleft Palate and Defective Osteogenesis

2018 ◽  
Vol 97 (13) ◽  
pp. 1485-1493 ◽  
Author(s):  
N.L. Hammond ◽  
K.J. Brookes ◽  
M.J. Dixon
Keyword(s):  
Cleft Palate ◽  
Hedgehog Signaling ◽  
Regulatory Networks ◽  
Neural Crest Cell ◽  
Bmp Signaling ◽  
The Novel ◽  
Morphogenetic Protein ◽  
Secondary Palate ◽  
Hh Signaling ◽  
Crest Cell

Cleft palate is a common birth defect that frequently occurs in human congenital malformations caused by mutations in components of the Sonic Hedgehog (S HH) signaling cascade. Shh is expressed in dynamic, spatiotemporal domains within epithelial rugae and plays a key role in driving epithelial-mesenchymal interactions that are central to development of the secondary palate. However, the gene regulatory networks downstream of Hedgehog (Hh) signaling are incompletely characterized. Here, we show that ectopic Hh signaling in the palatal mesenchyme disrupts oral-nasal patterning of the neural crest cell–derived ectomesenchyme of the palatal shelves, leading to defective palatine bone formation and fully penetrant cleft palate. We show that a series of Fox transcription factors, including the novel direct target Foxl1, function downstream of Hh signaling in the secondary palate. Furthermore, we demonstrate that Wnt/bone morphogenetic protein (BMP) antagonists, in particular Sostdc1, are positively regulated by Hh signaling, concomitant with downregulation of key regulators of osteogenesis and BMP signaling effectors. Our data demonstrate that ectopic Hh-Smo signaling downregulates Wnt/BMP pathways, at least in part by upregulating Sostdc1, resulting in cleft palate and defective osteogenesis.

scholarly journals Activation of hedgehog signaling associates with early disease progression in chronic lymphocytic leukemia

Blood ◽  
2019 ◽  
Vol 133 (25) ◽  
pp. 2651-2663 ◽  
Author(s):  
Emanuela M. Ghia ◽  
Laura Z. Rassenti ◽  
Donna S. Neuberg ◽  
Alejandro Blanco ◽  
Fouad Yousif ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Disease Progression ◽  
Hedgehog Signaling ◽  
Lymphocytic Leukemia ◽  
Early Disease ◽  
Mutation Status ◽  
Enhanced Sensitivity ◽  
Genes Encoding ◽  
Treatment Naïve ◽  
Hh Signaling

Abstract Targeted sequencing of 103 leukemia-associated genes in leukemia cells from 841 treatment-naive patients with chronic lymphocytic leukemia (CLL) identified 89 (11%) patients as having CLL cells with mutations in genes encoding proteins that putatively are involved in hedgehog (Hh) signaling. Consistent with this finding, there was a significant association between the presence of these mutations and the expression of GLI1 (χ2 test, P < .0001), reflecting activation of the Hh pathway. However, we discovered that 38% of cases without identified mutations also were GLI1+. Patients with GLI1+ CLL cells had a shorter median treatment-free survival than patients with CLL cells lacking expression of GLI1 independent of IGHV mutation status. We found that GANT61, a small molecule that can inhibit GLI1, was highly cytotoxic for GLI1+ CLL cells relative to that of CLL cells without GLI1. Collectively, this study shows that a large proportion of patients have CLL cells with activated Hh signaling, which is associated with early disease progression and enhanced sensitivity to inhibition of GLI1.

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