scholarly journals New Tricks for an Old (Hedge)Hog: Sonic Hedgehog Regulation of Astrocyte Function

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1353
Author(s):  
A. Denise R. Garcia
Keyword(s):  
Signaling Pathway ◽  
Sonic Hedgehog ◽  
Synapse Formation ◽  
Inflammatory Responses ◽  
Molecular Signaling ◽  
Synaptic Organization ◽  
Shh Signaling ◽  
Broad Array ◽  
And Function ◽  
Molecular Signaling Pathway

The Sonic hedgehog (Shh) molecular signaling pathway is well established as a key regulator of neurodevelopment. It regulates diverse cellular behaviors, and its functions vary with respect to cell type, region, and developmental stage, reflecting the incredible pleiotropy of this molecular signaling pathway. Although it is best understood for its roles in development, Shh signaling persists into adulthood and is emerging as an important regulator of astrocyte function. Astrocytes play central roles in a broad array of nervous system functions, including synapse formation and function as well as coordination and orchestration of CNS inflammatory responses in pathological states. Neurons are the source of Shh in the adult, suggesting that Shh signaling mediates neuron–astrocyte communication, a novel role for this multifaceted pathway. Multiple roles for Shh signaling in astrocytes are increasingly being identified, including regulation of astrocyte identity, modulation of synaptic organization, and limitation of inflammation. This review discusses these novel roles for Shh signaling in regulating diverse astrocyte functions in the healthy brain and in pathology.

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 Sonic hedgehog signaling in astrocytes mediates cell type-specific synaptic organization

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Steven A Hill ◽  
Andrew S Blaeser ◽  
Austin A Coley ◽  
Yajun Xie ◽  
Katherine A Shepard ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Neuronal Excitability ◽  
Synapse Formation ◽  
Critical Role ◽  
K Channel ◽  
Synaptic Organization ◽  
Cell Type ◽  
Shh Signaling ◽  
Cell Type Specific

Astrocytes have emerged as integral partners with neurons in regulating synapse formation and function, but the mechanisms that mediate these interactions are not well understood. Here, we show that Sonic hedgehog (Shh) signaling in mature astrocytes is required for establishing structural organization and remodeling of cortical synapses in a cell type-specific manner. In the postnatal cortex, Shh signaling is active in a subpopulation of mature astrocytes localized primarily in deep cortical layers. Selective disruption of Shh signaling in astrocytes produces a dramatic increase in synapse number specifically on layer V apical dendrites that emerges during adolescence and persists into adulthood. Dynamic turnover of dendritic spines is impaired in mutant mice and is accompanied by an increase in neuronal excitability and a reduction of the glial-specific, inward-rectifying K+ channel Kir4.1. These data identify a critical role for Shh signaling in astrocyte-mediated modulation of neuronal activity required for sculpting synapses.

scholarly journals Sonic hedgehog signaling in astrocytes mediates cell type-specific synaptic organization

2019 ◽  
Author(s):  
Steven Hill ◽  
Andrew Blaeser ◽  
Austin A. Coley ◽  
Yajun Xie ◽  
Katherine A. Shepard ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Neuronal Excitability ◽  
Synapse Formation ◽  
Critical Role ◽  
Synaptic Organization ◽  
Cell Type ◽  
Sonic Hedgehog Signaling ◽  
Shh Signaling ◽  
Cell Type Specific

Astrocytes have emerged as integral partners with neurons in regulating synapse formation and function, but the mechanisms that mediate these interactions are not well understood. Here, we show that Sonic hedgehog (Shh) signaling between neurons and astrocytes is required for establishing structural organization and remodeling of cortical synapses in a cell type-specific manner. In the postnatal cortex, Shh signaling is active in a subpopulation of mature astrocytes localized primarily in deep cortical layers. Selective disruption of Shh signaling in astrocytes produces a dramatic increase in synapse number specifically on layer V apical dendrites that emerges during adolescence and persists into adulthood. Dynamic turnover of dendritic spines is impaired in mutant mice and is accompanied by an increase in neuronal excitability and a reduction of the glial-specific, inward-rectifying K+ channel Kir4.1. These data identify a critical role for Shh signaling in astrocyte-mediated modulation of neuronal activity required for sculpting synapses.

Itraconazole Attenuates Peritoneal Fibrosis Through Its Effect on the Sonic Hedgehog Signaling Pathway in Mice

2018 ◽  
Vol 48 (6) ◽  
pp. 456-464 ◽  
Author(s):  
Jin Sug Kim ◽  
Kyung Sook Cho ◽  
Seon Hwa Park ◽  
Sang Ho Lee ◽  
Ji Hwan Lee ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Sonic Hedgehog ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Isotonic Saline ◽  
Control Group ◽  
Protective Effects ◽  
Peritoneal Fibrosis ◽  
Shh Signaling ◽  
Itraconazole Treatment

Background: Peritoneal fibrosis is a devastating complication of peritoneal dialysis. However, its precise mechanism is unclear, and specific treatments have not yet been established. Recent evidence suggests that the sonic hedgehog (SHH) signaling pathway is involved in tissue fibrogenesis. Drugs that inhibit this pathway are emerging in the field of anti-fibrosis therapy. Itraconazole, an anti-fungal agent, was also recently recognized as an inhibitor of the SHH signaling pathway. In this study, we used a mouse model to investigate whether the SHH signaling pathway is involved in the development of peritoneal fibrosis and the effects of itraconazole on peritoneal fibrosis. Methods: Peritoneal fibrosis was induced by intraperitoneal (IP) injection of 0.1% chlorhexidine gluconate (CG) solution every other day for 4 weeks, with or without itraconazole treatment (20 mg/kg, IP injection on a daily basis). Male C57BL/6 mice were divided into 4 groups: saline group, saline plus itraconazole group, CG group, and CG plus itraconazole group. Isotonic saline was administered intraperitoneally to the control group. The peritoneal tissues were evaluated for histological changes, expression of fibrosis markers, and the main components of the SHH signaling pathway. Results: Peritoneal thickening was evident in the CG group and was significantly decreased by itraconazole administration (80.4 ± 7.7 vs. 28.2 ± 3.8 µm, p < 0.001). The expression of the following SHH signaling pathway components was upregulated in the CG group and suppressed by itraconazole treatment: SHH, patched, smoothened, and glioma-associated oncogene transcription factor 1. The IP injection of CG solution increased the expression of fibrosis markers such as α-smooth muscle actin and transforming growth factor-β1 in the peritoneal tissues. Itraconazole treatment significantly decreased the expression of these markers. Conclusion: Our study provides the first evidence that the SHH signaling pathway may be implicated in peritoneal fibrosis. It also demonstrates that itraconazole treatment has protective effects on peritoneal fibrosis through the regulation of the SHH signaling pathway. These findings suggest that blockage of the SHH signaling pathway is a potential therapeutic strategy for peritoneal fibrosis.

scholarly journals Soluble Heparin and Heparan Sulfate Glycosaminoglycans Interfere with Sonic Hedgehog Solubilization and Receptor Binding

Molecules ◽  
2019 ◽  
Vol 24 (8) ◽  
pp. 1607 ◽  
Author(s):  
Manikowski ◽  
Jakobs ◽  
Jboor ◽  
Grobe
Keyword(s):  
Heparan Sulfate ◽  
Sonic Hedgehog ◽  
Receptor Binding ◽  
Feedback Loop ◽  
Cancer Cell Growth ◽  
Shh Signaling ◽  
Epithelial Cancers ◽  
And Function

Sonic hedgehog (Shh) signaling plays a tumor-promoting role in many epithelial cancers. Cancer cells produce soluble a Shh that signals to distant stromal cells that express the receptor Patched (Ptc). These receiving cells respond by producing other soluble factors that promote cancer cell growth, generating a positive feedback loop. To interfere with reinforced Shh signaling, we examined the potential of defined heparin and heparan sulfate (HS) polysaccharides to block Shh solubilization and Ptc receptor binding. We confirm in vitro and in vivo that proteolytic cleavage of the N-terminal Cardin–Weintraub (CW) amino acid motif is a prerequisite for Shh solubilization and function. Consistent with the established binding of soluble heparin or HS to the Shh CW target motif, both polysaccharides impaired proteolytic Shh processing and release from source cells. We also show that HS and heparin bind to, and block, another set of basic amino acids required for unimpaired Shh binding to Ptc receptors on receiving cells. Both modes of Shh activity downregulation depend more on HS size and overall charge than on specific HS sulfation modifications. We conclude that heparin oligosaccharide interference in the physiological roles of HS in Shh release and reception may be used to expand the field of investigation to pharmaceutical intervention of tumor-promoting Shh functions.

scholarly journals Baicalin improves the in vitro developmental capacity of pig embryos by inhibiting apoptosis, regulating mitochondrial activity and activating sonic hedgehog signaling

2019 ◽  
Vol 25 (9) ◽  
pp. 538-549 ◽  
Author(s):  
Qing Guo ◽  
Mei-Fu Xuan ◽  
Zhao-Bo Luo ◽  
Jun-Xia Wang ◽  
Sheng-Zhong Han ◽  
...  
Keyword(s):  
Embryonic Development ◽  
Signaling Pathway ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Control Group ◽  
Mitochondrial Activity ◽  
Cell Stage ◽  
Shh Signaling ◽  
Developmental Capacity

Abstract Baicalin, a traditional Chinese medicinal monomer whose chemical structure is known, can be used to treat female infertility. However, the effect of baicalin on embryonic development is unknown. This study investigated the effects of baicalin on in vitro development of parthenogenetically activated (PA) and in vitro fertilized (IVF) pig embryos and the underlying mechanisms involved. Treatment with 0.1 μg/ml baicalin significantly improved (P < 0.05) the in vitro developmental capacity of PA pig embryos by reducing the reactive oxygen species (ROS) levels and apoptosis and increasing the mitochondrial membrane potential (ΔΨm) and ATP level. mRNA and protein expression of sonic hedgehog (SHH) and GLI1, which are related to the SHH signaling pathway, in PA pig embryos at the 2-cell stage, were significantly higher in the baicalin-treated group than in the control group. To confirm that the SHH signaling pathway is involved in the mechanism by which baicalin improves embryonic development, we treated embryos with baicalin in the absence or presence of cyclopamine (Cy), an inhibitor of this pathway. Cy abolished the effects of baicalin on in vitro embryonic development. In conclusion, baicalin improves the in vitro developmental capacity of PA and IVF pig embryos by inhibiting ROS production and apoptosis, regulating mitochondrial activity and activating SHH signaling.

Astrocyte-neuron crosstalk through Hedgehog signaling mediates cortical circuit assembly

2020 ◽  
Author(s):  
Yajun Xie ◽  
Aaron T. Kuan ◽  
Wengang Wang ◽  
Zachary T. Herbert ◽  
Olivia Mosto ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Molecular Mechanisms ◽  
Synapse Formation ◽  
Critical Role ◽  
Shh Signaling ◽  
Shh Pathway ◽  
Cortical Astrocytes ◽  
Functional Features ◽  
And Function ◽  
Circuit Assembly

SUMMARYNeuron-glia relationships play a critical role in the regulation of synapse formation and neuronal specification. The cellular and molecular mechanisms by which neurons and astrocytes communicate and coordinate are not well understood. Here we demonstrate that the canonical Sonic hedgehog (Shh) pathway is active in cortical astrocytes, where it acts to coordinate layer-specific synaptic connectivity and functional circuit development. We show that Ptch1 is a Shh receptor that is expressed by cortical astrocytes during development and that Shh signaling is necessary and sufficient to promote the expression of layer-specific astrocyte genes involved in regulating synapse formation and function. Loss of Shh in layer V neurons reduces astrocyte complexity and coverage by astrocytic processes in tripartite synapses, moreover, cell-autonomous activation of Shh signaling in astrocytes promotes cortical excitatory synapse formation. Together, these results suggest that Shh secreted from deep layer cortical neurons acts to specialize the molecular and functional features of astrocytes during development to shape circuit assembly and function.

scholarly journals PSExplorer: whole parameter space exploration for molecular signaling pathway dynamics

2010 ◽  
Vol 26 (19) ◽  
pp. 2477-2479
Author(s):  
T. Q. Tung ◽  
D. Lee
Keyword(s):  
Signaling Pathway ◽  
Parameter Space ◽  
Space Exploration ◽  
Molecular Signaling ◽  
Molecular Signaling Pathway

scholarly journals Raman observation of a molecular signaling pathway of apoptotic cells induced by photothermal therapy

2019 ◽  
Vol 10 (47) ◽  
pp. 10900-10910 ◽  
Author(s):  
Yingfang Xing ◽  
Zhewei Cai ◽  
Meijuan Xu ◽  
Wenzheng Ju ◽  
Xiaojun Luo ◽  
...  
Keyword(s):  
Raman Spectroscopy ◽  
Signaling Pathway ◽  
Photothermal Therapy ◽  
Surface Enhanced Raman Spectroscopy ◽  
Apoptotic Cells ◽  
Molecular Signaling ◽  
Surface Enhanced ◽  
Surface Enhanced Raman ◽  
Molecular Signaling Pathway

A molecular signaling pathway of apoptosis induced by photothermal therapy was revealed by surface-enhanced Raman spectroscopy.

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