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 A subpopulation of astrocyte progenitors defined by Sonic hedgehog signaling

2022 ◽  
Vol 17 (1) ◽  
Author(s):  
Ellen C. Gingrich ◽  
Kendra Case ◽  
A. Denise R. Garcia
Keyword(s):  
Progenitor Cells ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Adult Brain ◽  
Substantial Contribution ◽  
Molecular Signaling ◽  
Sonic Hedgehog Signaling ◽  
Independent Manner ◽  
Shh Signaling ◽  
Cortical Astrocyte

Abstract Background The molecular signaling pathway, Sonic hedgehog (Shh), is critical for the proper development of the central nervous system. The requirement for Shh signaling in neuronal and oligodendrocyte development in the developing embryo are well established. However, Shh activity is found in discrete subpopulations of astrocytes in the postnatal and adult brain. Whether Shh signaling plays a role in astrocyte development is not well understood. Methods Here, we use a genetic inducible fate mapping approach to mark and follow a population of glial progenitor cells expressing the Shh target gene, Gli1, in the neonatal and postnatal brain. Results In the neonatal brain, Gli1-expressing cells are found in the dorsolateral corner of the subventricular zone (SVZ), a germinal zone harboring astrocyte progenitor cells. Our data show that these cells give rise to half of the cortical astrocyte population, demonstrating their substantial contribution to the cellular composition of the cortex. Further, these data suggest that the cortex harbors astrocytes from different lineages. Gli1 lineage astrocytes are distributed across all cortical layers, positioning them for broad influence over cortical circuits. Finally, we show that Shh activity recurs in mature astrocytes in a lineage-independent manner, suggesting cell-type dependent roles of the pathway in driving astrocyte development and function. Conclusion These data identify a novel role for Shh signaling in cortical astrocyte development and support a growing body of evidence pointing to astrocyte heterogeneity.

scholarly journals Gas1 Regulates Patterning of the Murine and Human Dentitions through Sonic Hedgehog

2021 ◽  
pp. 002203452110494
Author(s):  
M. Seppala ◽  
B. Thivichon-Prince ◽  
G.M. Xavier ◽  
N. Shaffie ◽  
I. Sangani ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Tooth Development ◽  
Human Subjects ◽  
Tooth Germ ◽  
Molecular Signaling ◽  
Loss Of Function ◽  
Supernumerary Teeth ◽  
Supernumerary Tooth ◽  
Tooth Number

The mammalian dentition is a serially homogeneous structure that exhibits wide numerical and morphological variation among multiple different species. Patterning of the dentition is achieved through complex reiterative molecular signaling interactions that occur throughout the process of odontogenesis. The secreted signaling molecule Sonic hedgehog (Shh) plays a key role in this process, and the Shh coreceptor growth arrest-specific 1 (Gas1) is expressed in odontogenic mesenchyme and epithelium during multiple stages of tooth development. We show that mice engineered with Gas1 loss-of-function mutation have variation in number, morphology, and size of teeth within their molar dentition. Specifically, supernumerary teeth with variable morphology are present mesial to the first molar with high penetrance, while molar teeth are characterized by the presence of both additional and absent cusps, combined with reduced dimensions and exacerbated by the presence of a supernumerary tooth. We demonstrate that the supernumerary tooth in Gas1 mutant mice arises through proliferation and survival of vestigial tooth germs and that Gas1 function in cranial neural crest cells is essential for the regulation of tooth number, acting to restrict Wnt and downstream FGF signaling in odontogenic epithelium through facilitation of Shh signal transduction. Moreover, regulation of tooth number is independent of the additional Hedgehog coreceptors Cdon and Boc, which are also expressed in multiple regions of the developing tooth germ. Interestingly, further reduction of Hedgehog pathway activity in Shhtm6Amc hypomorphic mice leads to fusion of the molar field and reduced prevalence of supernumerary teeth in a Gas1 mutant background. Finally, we demonstrate defective coronal morphology and reduced coronal dimensions in the molar dentition of human subjects identified with pathogenic mutations in GAS1 and SHH/GAS1, suggesting that regulation of Hedgehog signaling through GAS1 is also essential for normal patterning of the human dentition.

Cleft Palate and Aglossia Result from Perturbations in Wnt and Hedgehog Signaling

2017 ◽  
Vol 54 (3) ◽  
pp. 269-280 ◽  
Author(s):  
Gongjie Yuan ◽  
Gurpreet Singh ◽  
Serafine Chen ◽  
Kristy Carrington Perez ◽  
Yan Wu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Wnt Signaling ◽  
Primary Cilium ◽  
Molecular Basis ◽  
Hedgehog Signaling ◽  
Intraflagellar Transport ◽  
Molecular Signaling ◽  
A Cell ◽  
Cranial Neural Crest Cells ◽  
Facial Development

Objective The objective of this study was to explore the molecular basis for cleft secondary palate and arrested tongue development caused by the loss of the intraflagellar transport protein, Kif3a. Design Kif3a mutant embryos and their littermate controls were analyzed for defects in facial development at multiple stages of embryonic development. Histology was employed to understand the effects of Kif3a deletion on palate and tongue development. Various transgenic reporter strains were used to understand how deletion of Kif3a affected Hedgehog and Wnt signaling. Immunostaining for structural elements of the tongue and for components of the Wnt pathway were performed. BrdU activity analyses were carried out to examine how the loss of Kif3a affected cell proliferation and led to palate and tongue malformations. Results Kif3a deletion causes cranial neural crest cells to become unresponsive to Hedgehog signals and hyper-responsive to Wnt signals. This aberrant molecular signaling causes abnormally high cell proliferation, but paradoxically outgrowths of the tongue and the palatal processes are reduced. The basis for this enigmatic effect can be traced back to a disruption in epithelial/mesenchymal signaling that governs facial development. Conclusion The primary cilium is a cell surface organelle that integrates Hh and Wnt signaling, and disruptions in the function of the primary cilium cause one of the most common—of the rarest—craniofacial birth defects observed in humans. The shared molecular basis for these dysmorphologies is an abnormally high Wnt signal simultaneous with an abnormally low Hedgehog signal. These pathways are integrated in the primary cilium.

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 Sonic hedgehog signaling in astrocytes

2020 ◽  
Author(s):  
Steven A. Hill ◽  
Marissa Fu ◽  
A. Denise R. Garcia
Keyword(s):  
Nervous System ◽  
Signaling Pathway ◽  
Functional Properties ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Synapse Formation ◽  
Synaptic Activity ◽  
Molecular Signaling ◽  
Sonic Hedgehog Signaling ◽  
Shh Signaling

Abstract Astrocytes are complex cells that perform a broad array of essential functions in the healthy and injured nervous system. The recognition that these cells are integral components of various processes, including synapse formation, modulation of synaptic activity, and response to injury, underscores the need to identify the molecular signaling programs orchestrating these diverse functional properties. Emerging studies have identified the Sonic hedgehog (Shh) signaling pathway as an essential regulator of the molecular identity and functional properties of astrocytes. Well established as a powerful regulator of diverse neurodevelopmental processes in the embryonic nervous system, its functional significance in astrocytes is only beginning to be revealed. Notably, Shh signaling is active only in discrete subpopulations of astrocytes distributed throughout the brain, a feature that has potential to yield novel insights into functional specialization of astrocytes. Here, we discuss Shh signaling and emerging data that point to essential roles for this pleiotropic signaling pathway in regulating various functional properties of astrocytes in the healthy and injured brain.

scholarly journals YAP is involved in replenishment of granule cell progenitors following injury to the neonatal cerebellum

2019 ◽  
Author(s):  
Zhaohui Yang ◽  
Alexandra L. Joyner
Keyword(s):  
Granule Cell ◽  
Hedgehog Signaling ◽  
Hippo Pathway ◽  
Initial Step ◽  
Granule Cell Layer ◽  
Binding Motif ◽  
Hippo Signaling ◽  
Molecular Signaling ◽  
Sonic Hedgehog Signaling ◽  
Full Spectrum

ABSTRACTThe cerebellum (CB) undergoes major rapid growth during the third trimester and early neonatal stage in humans, making it vulnerable to injuries in pre-term babies. Experiments in mice have revealed a remarkable ability of the neonatal CB to recover from injuries around birth. In particular, recovery following irradiation-induced ablation of granule cell precursors (GCPs) involves adaptive reprogramming of Nestin-expressing glial progenitors (NEPs). Sonic hedgehog signaling is required for the initial step in NEP reprogramming; however, the full spectrum of developmental signaling pathways that promote NEP-driven regeneration is not known. Since the growth regulatory Hippo pathway has been implicated in the repair of several tissue types, we tested whether Hippo signaling is involved in regeneration of the CB. Using mouse models, we found that the Hippo pathway transcriptional co-activator YAP (Yes-associated protein) but not TAZ (transcriptional coactivator with PDZ binding motif) is required in NEPs for full recovery of the CB following irradiation one day after birth. The size of the adult CB, and in particular the internal granule cell layer produced by GCPs, is significantly reduced in mutants, and the organization of Purkinje cells and Bergmann glial fibers is disrupted. Surprisingly, the initial proliferative response of Yap mutant NEPs to irradiation is normal and the cells migrate to the GCP niche, but then undergo increased cell death. Loss of Yap in NEPs or GCPs during normal development leads to only mild defects in differentiation. Moreover, loss of Taz does not abrogate regeneration of GCPs by Yap mutant NEPs or alter development of the cerebellum. Our study provides new insights into the molecular signaling underlying postnatal cerebellar development and regeneration.

scholarly journals A subpopulation of astrocyte progenitors defined by Sonic hedgehog signaling

2020 ◽  
Author(s):  
Ellen Gingrich ◽  
Kendra Case ◽  
A. Denise R. Garcia
Keyword(s):  
Progenitor Cells ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Molecular Signaling ◽  
Sonic Hedgehog Signaling ◽  
Shh Signaling ◽  
Cortical Astrocyte ◽  
Germinal Zone ◽  
The Central Nervous System ◽  
Oligodendrocyte Development

ABSTRACTThe molecular signaling pathway, Sonic hedgehog (Shh), is critical for the proper development of the central nervous system. The requirement for Shh signaling in neuronal and oligodendrocyte development in the developing embryo are well established. Here, we show that Shh signaling also operates in a subpopulation of progenitor cells that generate cortical astrocytes. In the neonatal brain, cells expressing the Shh target gene, Gli1, are found in the subventricular zone (SVZ), a germinal zone harboring astrocyte progenitor cells. Using a genetic inducible fate mapping strategy, we show that these cells give rise to half of the cortical astrocyte population, suggesting that the cortex harbors astrocytes from different lineages. Shh activity in SVZ progenitor cells is transient but recurs in a subpopulation of mature astrocytes localized in layers IV and V in a manner independent of their lineage. These data identify a novel role for Shh signaling in cortical astrocyte development and support a growing body of evidence pointing to astrocyte heterogeneity.

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.

667: Sonic Hedgehog Signaling Plays a Pivotal Role in the Vicious Cycle between Human Prostate Cancer and Normal/Benign but not Cancer Associated Human Prostate Stromal Cells

2007 ◽  
Vol 177 (4S) ◽  
pp. 224-224
Author(s):  
Katsumi Shigemura ◽  
Wen-Chin Haung ◽  
Fray F. Marshall ◽  
Haiyen E. Zhau ◽  
Leland W.K. Chung ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Sonic Hedgehog ◽  
Stromal Cells ◽  
Hedgehog Signaling ◽  
Pivotal Role ◽  
Human Prostate ◽  
Human Prostate Cancer ◽  
Vicious Cycle ◽  
Sonic Hedgehog Signaling
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