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 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 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.

scholarly journals Identification of electrophysiologically distinct cell subpopulations in Necturus taste buds.

1993 ◽  
Vol 102 (1) ◽  
pp. 143-170 ◽  
Author(s):  
A Bigiani ◽  
S D Roper
Keyword(s):  
Lucifer Yellow ◽  
Taste Buds ◽  
Taste Bud ◽  
Basal Cells ◽  
Patch Clamp Technique ◽  
Lingual Epithelium ◽  
Voltage Gated ◽  
Receptor Cells ◽  
Taste Cells ◽  
K Currents

We used the patch clamp technique to record from taste cells in thin transverse slices of lingual epithelium from Necturus maculosus. In this preparation, the epithelial polarity and the cellular organization of the taste buds, as well as the interrelationships among cells within the taste bud, were preserved. Whole-cell recording, combined with cell identification using Lucifer yellow, allowed us to identify distinct subpopulations of taste cells based on their electrophysiological properties. Receptor cells could be divided in two groups: one group was characterized by the presence of voltage-gated Na+, K+, and Ca2+ currents; the other group was characterized by the presence of K+ currents only. Therefore, receptor cells in the first group would be expected to be capable of generating action potentials, whereas receptor cells in the second group would not. Basal taste cells could also be divided into two different groups. Some basal cells possessed voltage-gated Na+, K+, and Ca2+ conductances, whereas other basal cells only had K+ conductance. In addition to single taste cells, we were able to identify electrically coupled taste cells. We monitored cell-cell coupling by measuring membrane capacitance and by observing Lucifer yellow dye coupling. Electrical coupling in pairs of dye-coupled taste receptor cells was strong, as indicated by experiments with the uncoupling agent 1-octanol. Electrically coupled receptor cells possessed voltage-gated currents, including Na+ and K+ currents. The electrophysiological differentiation among taste cells presumably is related to functional diversifications, such as different chemosensitivities.

Hedgehog Signaling Is Dispensable for Adult Murine Hematopoiesis and Leukemogenesis.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1391-1391
Author(s):  
Inga Hofmann Zhang ◽  
Elizabeth H. Stover ◽  
Dana E. Cullen ◽  
Junhao Mao ◽  
Kelly J. Morgan ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Cell Fate ◽  
Intracellular Signaling ◽  
Hedgehog Signaling ◽  
Unexpected Finding ◽  
Hematopoietic Stem ◽  
Developmental Abnormalities ◽  
Hh Signaling ◽  
Pharmacologic Inhibition

Abstract Hedgehog (Hh) pathway proteins are a highly conserved family of intracellular signaling molecules that are critical for the development of multiple organs and tissues, and play a role in cell fate determination of self-renewing tissues in the adult. Mutations that impair Hh signaling have been associated with developmental abnormalities, and recent studies indicate that Hh plays an important role in hemangioblast formation and in adult hematopoiesis, as well as in the differentiation and proliferation of hematopoietic stem cells (HSC) and progenitor cells. We used a genetic and pharmacologic approach to define the role of the Hh pathway in adult hematopoiesis and leukemogenesis. We report the unexpected finding that loss of Hh signaling through conditional deletion of Smoothened (Smo) in the adult hematopoietic compartment has no effect on adult hematopoiesis, including peripheral blood count, number or cell cycle status of stem and progenitor cells, hematopoietic colony forming potential, long-term repopulating activity in competitive repopulation assays, or stress-response to serial 5-fluorouracil treatment. In support of these observations based on genetic inactivation of the pathway, we observed that pharmacologic inhibition of Hh signaling with a potent and highly selective small molecule antagonist of Smo has no apparent effect on hematopoiesis in the mouse in vivo. In addition, we observed that Hh signaling is not required for the development of MLL-AF9 mediated leukemia. Taken together, these data indicate that Hh signaling is dispensable for normal hematopoietic development and leukemogenesis, and that pharmacologic inhibition of Hh signaling, as a therapeutic strategy in treatment of solid tumors with constitutive Hh pathway activation is not likely to be associated with unmanageable hematopoietic toxicity.

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 Insulin Is Transcribed and Translated in Mammalian Taste Bud Cells

Endocrinology ◽  
2018 ◽  
Vol 159 (9) ◽  
pp. 3331-3339 ◽  
Author(s):  
Máire E Doyle ◽  
Jennifer L Fiori ◽  
Isabel Gonzalez Mariscal ◽  
Qing-Rong Liu ◽  
Erin Goodstein ◽  
...  
Keyword(s):  
Green Fluorescence Protein ◽  
Taste Buds ◽  
Taste Bud ◽  
Lingual Epithelium ◽  
Processing Enzymes ◽  
Taste Cells ◽  
Specific Proteins ◽  
Fluorescence Protein ◽  
Taste Bud Cells

Abstract We and others have reported that taste cells in taste buds express many peptides in common with cells in the gut and islets of Langerhans in the pancreas. Islets and taste bud cells express the hormones glucagon and ghrelin, the same ATP-sensitive potassium channel responsible for depolarizing the insulin-secreting β cell during glucose-induced insulin secretion, as well as the propeptide-processing enzymes PC1/3 and PC2. Given the common expression of functionally specific proteins in taste buds and islets, it is surprising that no one has investigated whether insulin is synthesized in taste bud cells. Using immunofluorescence, we demonstrated the presence of insulin in mouse, rat, and human taste bud cells. By detecting the postprocessing insulin molecule C-peptide and green fluorescence protein (GFP) in taste cells of both insulin 1-GFP and insulin 2-GFP mice and the presence of the mouse insulin transcript by in situ hybridization, we further proved that insulin is synthesized in individual taste buds and not taken up from the parenchyma. In addition to our cytology data, we measured the level of insulin transcript by quantitative RT-PCR in the anterior and posterior lingual epithelia. These analyses showed that insulin is translated in the circumvallate and foliate papillae in the posterior, but only insulin transcript was detected in the anterior fungiform papillae of the rodent tongue. Thus, some taste cells are insulin-synthesizing cells generated from a continually replenished source of precursor cells in the adult mammalian lingual epithelium.

Some Observations on Changes in Denervated Taste Buds of Circumvallate Papillae of Rabbits

1969 ◽  
Vol 27 ◽  
pp. 308-309
Author(s):  
Sunao Fujimoto ◽  
Raymond G. Murray ◽  
Assia Murray
Keyword(s):  
Taste Buds ◽  
Taste Bud ◽  
Cell Type ◽  
Dark Cells ◽  
Type Iii ◽  
Circumvallate Papillae ◽  
Taste Bud Cells ◽  
Light Cells

Taste bud cells in circumvallate papillae of rabbit have been classified into three groups: dark cells; light cells; and type III cells. Unilateral section of the 9th nerve distal to the petrosal ganglion was performed in 18 animals, and changes of each cell type in the denervated buds were observed from 6 hours to 10 days after the operation.Degeneration of nerves is evident at 12 hours (Fig. 1) and by 2 days, nerves are completely lacking in the buds. Invasion by leucocytes into the buds is remarkable from 6 to 12 hours but then decreases. Their extrusion through the pore is seen. Shrinkage and disturbance in arrangement of cells in the buds can be seen at 2 days. Degenerated buds consisting of a few irregular cells and remnants of degenerated cells are present at 4 days, but buds apparently normal except for the loss of nerve elements are still present at 6 days.

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

Lingual deficits in BDNF and NT3 mutant mice leading to gustatory and somatosensory disturbances, respectively

Development ◽  
1997 ◽  
Vol 124 (7) ◽  
pp. 1333-1342 ◽  
Author(s):  
C.A. Nosrat ◽  
J. Blomlof ◽  
W.M. ElShamy ◽  
P. Ernfors ◽  
L. Olson
Keyword(s):  
Taste Buds ◽  
Mutant Mice ◽  
Taste Bud ◽  
Physiological Data ◽  
Clinical Implications ◽  
Wild Type ◽  
Severe Reduction ◽  
Sensory Modalities ◽  
Per Se ◽  
Taste Discrimination

A combination of anatomical, histological and physiological data from wild-type and null-mutated mice have established crucial roles for BDNF and NT3 in gustatory and somatosensory innervation of the tongue, and indeed for proper development of the papillary surface of the tongue. BDNF is expressed in taste buds, NT3 in many surrounding epithelial structures. Absence of BDNF in mice leads to severely malformed taste bud-bearing papillae and severe reduction of taste buds, a loss of proper innervation of remaining taste buds and a loss of taste discrimination although not of the suckling reflex per se. In contrast, absence of NT3 leads to a massive loss of somatosensory innervation of lingual structures. These findings demonstrate distinct roles for BDNF and NT3 in the establishment of the complex innervation apparatus of the tongue with non-overlapping roles for the lingual gustatory and somatosensory systems. The distinction between different sensory modalities, being dependent on either BDNF or NT3 may also have clinical implications.

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.

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