scholarly journals Multifaceted functions of Rab23 on primary cilium and Hedgehog signaling-mediated granule cell proliferation

2020 ◽  
Author(s):  
CHH Hor ◽  
WY Leong ◽  
ELK Goh
Keyword(s):  
Sonic Hedgehog ◽  
Primary Cilium ◽  
Granule Cell ◽  
Hedgehog Signaling ◽  
Cell Precursor ◽  
Shh Signaling ◽  
Shh Pathway ◽  
Granule Cell Precursor

AbstractSonic Hedgehog (Shh) signaling from the primary cilium drives cerebellar granule cell precursor (GCP) proliferation. Mutations of hedgehog (Hh) pathway repressors could cause medulloblastoma, the most prevalent and malignant childhood brain tumor that arises from aberrant GCP proliferation. We demonstrate that brain-specific knockout of a Shh pathway repressor Rab23 in mice caused mis-patterning of cerebellar folia and elevated GCP proliferation during early development, but with no prevalent occurrence of medulloblastoma at adult stage. Strikingly, Rab23-depleted GCPs exhibited up-regulated basal level of Shh pathway activities despite reduced ciliation, and were desensitized against stimulations by Shh and Smoothened (Smo) agonist in primary GCP culture. These results illustrate dual functions of Rab23 in repressing the basal level of Shh signaling, while facilitating Shh signal transduction via Shh/Smo on primary cilium. Collectively, our findings unravel instrumental roles of Rab23 in GCP proliferation and ciliogenesis. Rab23’s potentiation of Shh signaling pathway through the primary cilium and Smo, suggests a potential new therapeutic for Smo/primary cilium-driven medulloblastoma.Author SummaryC.H.H conceived, designed, lead, and performed all in vitro and in vivo experiments, analyzed data and wrote the manuscript. W.Y performed QPCR experiments and primary GCP cultures and analyzed data. E.L.G conceived and directed the study.

FoxF1 is Required for Ciliogenesis and Distribution of Sonic Hedgehog Signaling Components in Cilium

2019 ◽  
Vol 19 (5) ◽  
pp. 326-334
Author(s):  
Lu Huang ◽  
Marco Tjakra ◽  
Desha Luo ◽  
Lin Wen ◽  
Daoxi Lei ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
3T3 Cells ◽  
Shh Signaling ◽  
Nih 3T3 ◽  
Signaling Components ◽  
Nih 3T3 Cells

Background: In vertebrates, cilium is crucial for Hedgehog signaling transduction. Forkhead box transcriptional factor FoxF1 is reported to be associated with Sonic Hedgehog (Shh) signaling in many cases. However, the role of FoxF1 in cilium remains unknown. Here, we showed an essential role of FoxF1 in the regulation of ciliogenesis and in the distribution of Shh signaling components in cilium. Methods: NIH/3T3 cells were serum starved for 24h to induce cilium. Meanwhile, shRNA was used to knockdown the FoxF1 expression in the cells and CRISPR/Cas9 was used to generate the FoxF1 zebrafish mutant. The mRNA and protein expression of indicated genes were detected by the qRT-PCR and western blot, respectively. Immunofluorescence staining was performed to detect the cilium and Shh components distribution. Results: FoxF1 knockdown decreased the cilium length in NIH/3T3 cells. Meanwhile, the disruption of FoxF1 function inhibited the expression of cilium-related genes and caused an abnormal distribution of Shh components in the cilium. Furthermore, homozygous FoxF1 mutants exhibited defective development of pronephric cilium in early zebrafish embryos. Conclusion: Together, our data illustrated that FoxF1 is required for ciliogenesis in vitro and in vivo and for the proper localization of Shh signaling components in cilium.

scholarly journals Sonic Hedgehog Signaling Drives Proliferation of Synoviocytes in Rheumatoid Arthritis: A Possible Novel Therapeutic Target

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Mingxia Wang ◽  
Shangling Zhu ◽  
Weixiang Peng ◽  
Qiuxia Li ◽  
Zhaoxia Li ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Sonic Hedgehog ◽  
Therapeutic Target ◽  
Hedgehog Signaling ◽  
Specific Inhibitor ◽  
Sonic Hedgehog Signaling ◽  
Shh Signaling ◽  
Novel Therapeutic

Sonic hedgehog (Shh) signaling controls many aspects of human development, regulates cell growth and differentiation in adult tissues, and is activated in a number of malignancies. Rheumatoid arthritis (RA) is characterized by chronic synovitis and pannus formation associated with activation of fibroblast-like synoviocytes (FLS). We investigated whether Shh signaling plays a role in the proliferation of FLS in RA. Expression of Shh signaling related components (Shh, Ptch1, Smo, and Gli1) in RA synovial tissues was examined by immunohistochemistry (IHC) and in FLS by IHC, immunofluorescence (IF), quantitative RT-PCR, and western blotting. Expression of Shh, Smo, and Gli1 in RA synovial tissue was higher than that in control tissue (P<0.05). Cyclopamine (a specific inhibitor of Shh signaling) decreased mRNA expression of Shh, Ptch1, Smo, and Gli1 in cultured RA FLS, Shh, and Smo protein expression, and significantly decreased FLS proliferation. Flow cytometry analysis suggested that cyclopamine treatment resulted in cell cycle arrest of FLS in G1phase. Our data show that Shh signaling is activated in synovium of RA patientsin vivoand in cultured FLS form RA patientsin vitro, suggesting a role in the proliferation of FLS in RA. It may therefore be a novel therapeutic target in RA.

Sonic hedgehog-dependent emergence of oligodendrocytes in the telencephalon: evidence for a source of oligodendrocytes in the olfactory bulb that is independent of PDGFRα signaling

Development ◽  
2001 ◽  
Vol 128 (24) ◽  
pp. 4993-5004
Author(s):  
Nathalie Spassky ◽  
Katharina Heydon ◽  
Arnaud Mangatal ◽  
Alexandar Jankovski ◽  
Christelle Olivier ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Olfactory Bulb ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Molecular Mechanisms ◽  
Cell Contact ◽  
Sonic Hedgehog Signaling ◽  
Oligodendrocyte Progenitors

Most studies on the origin of oligodendrocyte lineage have been performed in the spinal cord. By contrast, molecular mechanisms that regulate the appearance of the oligodendroglial lineage in the brain have not yet attracted much attention. We provide evidence for three distinct sources of oligodendrocytes in the mouse telencephalon. In addition to two subpallial ventricular foci, the anterior entopeduncular area and the medial ganglionic eminence, the rostral telencephalon also gives rise to oligodendrocytes. We show that oligodendrocytes in the olfactory bulb are generated within the rostral pallium from ventricular progenitors characterized by the expression of Plp. We provide evidence that these Plp oligodendrocyte progenitors do not depend on signal transduction mediated by platelet-derived growth factor receptors (PDGFRs), and therefore propose that they belong to a different lineage than the PDGFRα-expressing progenitors. Moreover, induction of oligodendrocytes in the telencephalon is dependent on sonic hedgehog signaling, as in the spinal cord. In all these telencephalic ventricular territories, oligodendrocyte progenitors were detected at about the same developmental stage as in the spinal cord. However, both in vivo and in vitro, the differentiation into O4-positive pre-oligodendrocytes was postponed by 4-5 days in the telencephalon in comparison with the spinal cord. This delay between determination and differentiation appears to be intrinsic to telencephalic oligodendrocytes, as it was not shortened by diffusible or cell-cell contact factors present in the spinal cord.

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.

scholarly journals Dihydroartemisinin Sensitizes Esophageal Squamous Cell Carcinoma to Cisplatin by Inhibiting Sonic Hedgehog Signaling

2020 ◽  
Vol 8 ◽  
Author(s):  
Wei Cui ◽  
Tingting Fang ◽  
Zhaoheng Duan ◽  
Dongfang Xiang ◽  
Yanxia Wang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Continuous Treatment ◽  
Shh Signaling ◽  
Shh Pathway

Platinum-based regimens have been routinely used in the clinical treatment of patients with esophageal squamous cell carcinoma (ESCC). However, administration of these drugs is frequently accompanied by drug resistance. Revealing the underlying mechanisms of the drug resistance and developing agents that enhance the sensitivity to platinum may provide new therapeutic strategies for the patients. In the present study, we found that the poor outcome of ESCC patients receiving platinum-based regimens was associated with co-expression of Shh and Sox2. The sensitivity of ESCC cell lines to cisplatin was related to their activity of Shh signaling. Manipulating of Shh expression markedly changed the sensitivity of ESCC cells to platinum. Continuous treatment with cisplatin resulted in the activation of Shh signaling and enhanced cancer stem cell-like phenotypes in ESCC cells. Dihydroartemisinin (DHA), a classic antimalarial drug, was identified as a novel inhibitor of Shh pathway. Treatment with DHA attenuated the cisplatin-induced activation of the Shh pathway in ESCC cells and synergized the inhibitory effect of cisplatin on proliferation, sphere and colony formation of ALDH-positive ESCC cells in vitro and growth of ESCC cell-derived xenograft tumors in vivo. Taken together, these results demonstrate that the Shh pathway is an important player in cisplatin-resistant ESCC and DHA acts as a promising therapeutic agent to sensitize ESCC to cisplatin treatment.

scholarly journals Sonic hedgehog signaling in epithelial tissue development

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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