Sonic hedgehog signaling in astrocytes

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.

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

Cells ◽

10.3390/cells10061353 ◽

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.

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Sonic hedgehog signaling in epithelial tissue development

Regenerative Medicine Research ◽

10.1051/rmr/190004 ◽

2019 ◽

Vol 7 ◽

pp. 3

Author(s):

Lu Zheng ◽

Chen Rui ◽

Hao Zhang ◽

Jing Chen ◽

Xiuzhi Jia ◽

...

Keyword(s):

Signaling Pathway ◽

Sonic Hedgehog ◽

Hedgehog Signaling ◽

Gastric Epithelium ◽

Epithelial Tissue ◽

Sonic Hedgehog Signaling ◽

Shh Signaling ◽

Shh Pathway ◽

Tissue Repair And Regeneration ◽

New Treatment

The Sonic hedgehog (SHH) signaling pathway is essential for embryonic development and tissue regeneration. The dysfunction of SHH pathway is involved in a variety of diseases, including cancer, birth defects, and other diseases. Here we reviewed recent studies on main molecules involved in the SHH signaling pathway, specifically focused on their function in epithelial tissue and appendages development, including epidermis, touch dome, hair, sebaceous gland, mammary gland, tooth, nail, gastric epithelium, and intestinal epithelium. The advance in understanding the SHH signaling pathway will give us more clues to the mechanisms of tissue repair and regeneration, as well as the development of new treatment for diseases related to dysregulation of SHH signaling pathway.

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A subpopulation of astrocyte progenitors defined by Sonic hedgehog signaling

Neural Development ◽

10.1186/s13064-021-00158-w ◽

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.

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Sonic Hedgehog Signaling Pathway in Endothelial Progenitor Cell Biology for Vascular Medicine

International Journal of Molecular Sciences ◽

10.3390/ijms19103040 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3040 ◽

Cited By ~ 6

Author(s):

Amankeldi A. Salybekov ◽

Ainur K. Salybekova ◽

Roberto Pola ◽

Takayuki Asahara

Keyword(s):

Cardiovascular Diseases ◽

Signaling Pathway ◽

Sonic Hedgehog ◽

Cell Biology ◽

Hedgehog Signaling ◽

Signal Transmission ◽

Vascular Medicine ◽

Endothelial Progenitor ◽

Sonic Hedgehog Signaling ◽

Shh Signaling

The Hedgehog (HH) signaling pathway plays an important role in embryonic and postnatal vascular development and in maintaining the homeostasis of organs. Under physiological conditions, Sonic Hedgehog (SHH), a secreted protein belonging to the HH family, regulates endothelial cell growth, promotes cell migration and stimulates the formation of new blood vessels. The present review highlights recent advances made in the field of SHH signaling in endothelial progenitor cells (EPCs). The canonical and non-canonical SHH signaling pathways in EPCs and endothelial cells (ECs) related to homeostasis, SHH signal transmission by extracellular vesicles (EVs) or exosomes containing single-strand non-coding miRNAs and impaired SHH signaling in cardiovascular diseases are discussed. As a promising therapeutic tool, the possibility of using the SHH signaling pathway for the activation of EPCs in patients suffering from cardiovascular diseases is further explored.

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Sonic Hedgehog Signaling in Organogenesis, Tumors, and Tumor Microenvironments

International Journal of Molecular Sciences ◽

10.3390/ijms21030758 ◽

2020 ◽

Vol 21 (3) ◽

pp. 758 ◽

Cited By ~ 12

Author(s):

Kuo-Shyang Jeng ◽

Chiung-Fang Chang ◽

Shu-Sheng Lin

Keyword(s):

Tumor Microenvironment ◽

Signaling Pathway ◽

Sonic Hedgehog ◽

Cancer Progression ◽

Hedgehog Signaling ◽

Primary Cilia ◽

Tumor Development ◽

Sonic Hedgehog Signaling ◽

Shh Signaling ◽

Tumor Microenvironments

During mammalian embryonic development, primary cilia transduce and regulate several signaling pathways. Among the various pathways, Sonic hedgehog (SHH) is one of the most significant. SHH signaling remains quiescent in adult mammalian tissues. However, in multiple adult tissues, it becomes active during differentiation, proliferation, and maintenance. Moreover, aberrant activation of SHH signaling occurs in cancers of the skin, brain, liver, gallbladder, pancreas, stomach, colon, breast, lung, prostate, and hematological malignancies. Recent studies have shown that the tumor microenvironment or stroma could affect tumor development and metastasis. One hypothesis has been proposed, claiming that the pancreatic epithelia secretes SHH that is essential in establishing and regulating the pancreatic tumor microenvironment in promoting cancer progression. The SHH signaling pathway is also activated in the cancer stem cells (CSC) of several neoplasms. The self-renewal of CSC is regulated by the SHH/Smoothened receptor (SMO)/Glioma-associated oncogene homolog I (GLI) signaling pathway. Combined use of SHH signaling inhibitors and chemotherapy/radiation therapy/immunotherapy is therefore key in targeting CSCs.

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

10.1101/537860 ◽

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.

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Abstract WMP36: The Sonic Hedgehog Signaling Pathway Mediates Cerebrolysin-Improved Neurological Functions after Stroke

Stroke ◽

10.1161/str.44.suppl_1.awmp36 ◽

2013 ◽

Vol 44 (suppl_1) ◽

Author(s):

Li Zhang ◽

Michael Chopp ◽

Zheng Gang Zhang

Keyword(s):

Signaling Pathway ◽

Sonic Hedgehog ◽

Functional Recovery ◽

Hedgehog Signaling ◽

Artery Occlusion ◽

Vehicle Group ◽

Sonic Hedgehog Signaling ◽

Shh Signaling ◽

Stroke Treatment ◽

Shh Pathway

Cerebrolysin, a mixture of neurotrophic peptides, enhances neurogenesis in experimental neurodegenerative diseases and stroke. Sonic hedgehog (Shh) signaling pathway stimulates neurogenesis after stroke. In the present study, we tested the hypothesis that the Shh signaling pathway mediates Cerebrolysin enhanced neurogenesis and functional recovery after stroke. Rats were subjected to embolic middle cerebral artery occlusion (MCAo). To examine whether blockage of the Shh signaling pathway abolishes the Cerebrolysin induced neurogenesis and functional recovery, Cyclopamine (0.2mg/kg), a Shh receptor inhbitor, or vehicle (45% 2-hydroxypropyl-cyclodextrin) was intraventricularly infused using an osmotic pump for 28 days starting 24h after MCAo with or without intraperitoneally (IP) administration of Cerebrolysin (2.5ml/kg, daily for 28d). For mitotic labeling, Bromodeoxyuridine (BrdU, 100mg/kg, IP) was administered daily for 7 days starting 24h after MCAo. Neurological functional tests including, adhesive removal test, foot-fault test, and modified neurological severity score (mNSS) were performed weekly for 5 weeks after stroke. Treatment with Cerebrolysin significantly (p<0.05) increased the number of BrdU positive cells (148±24/mm 2 vs 90±9/mm 2 in the vehicle group, n=10/group) in the ipsilateral subventricular zone (SVZ), which was associated with significant improvement of functional recovery from week 3 thought week 5 after MCAo compared with vehicle treated rats. However, inhibition of the Shh pathway with Cyclopamine significantly reduced BrdU positive cells (51±10/mm 2 ) in the SVZ, and cyclopamine treated animals failed to improve neurological function compared with vehicle treated rats. Furthermore, Cyclopamine completely reversed the effects of Cerebrolysin on SVZ cell proliferation (90±10/mm 2 ) and functional recovery. These results demonstrate that the Shh pathway mediates Cerebrolysin-enhanced neural progenitor proliferation and improves functional recovery in rats after stroke.

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Sonic Hedgehog Signaling Pathway in Endothelial Progenitor Cell Biology for Vascular Medicine

10.20944/preprints201808.0110.v2 ◽

2018 ◽

Author(s):

Amankeldi A. Salybekov ◽

Ainur K. Salybekova ◽

Roberto Pola ◽

Takayuki Asahara

Keyword(s):

Cardiovascular Diseases ◽

Signaling Pathway ◽

Sonic Hedgehog ◽

Cell Biology ◽

Hedgehog Signaling ◽

Signal Transmission ◽

Vascular Medicine ◽

Endothelial Progenitor ◽

Sonic Hedgehog Signaling ◽

Shh Signaling

The Hedgehog (Hh) signaling pathway plays an important role in embryonic and postnatal vascular development and in maintaining the homeostasis of organs. Under physiological conditions, Sonic Hedgehog (Shh), a secreted protein belonging to the Hh family, regulates endothelial cell growth, promotes cell migration, and stimulates the formation of new blood vessels. The present review highlights recent advances made in the field of Shh signaling in endothelial progenitor cells (EPCs). The canonical and non-canonical Shh signaling pathways in EPCs and endothelial cells (ECs) related to homeostasis, Shh signal transmission by extracellular vesicles (EVs) or exosomes containing single-strand non-coding miRNAs, and impaired Shh signaling in cardiovascular diseases are discussed. As a promising therapeutic tool, the possibility of using the Shh signaling pathway for the activation of EPCs in patients suffering from cardiovascular diseases is further explored.

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A subpopulation of astrocyte progenitors defined by Sonic hedgehog signaling

10.1101/2020.06.17.157065 ◽

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.

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