scholarly journals The stem cell-associated transcription co-factor, ZNF521, interacts with GLI1 and GLI2 and enhances the activity of the Sonic hedgehog pathway

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Stefania Scicchitano ◽  
Marco Giordano ◽  
Valeria Lucchino ◽  
Ylenia Montalcini ◽  
Emanuela Chiarella ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Transcriptional Activation ◽  
Neural Progenitor Cells ◽  
Binding Motif ◽  
Nurd Complex ◽  
Sonic Hedgehog Pathway ◽  
Substantial Fraction ◽  
Regulatory Functions ◽  
Normal Cerebellum

Abstract ZNF521 is a transcription co-factor with recognized regulatory functions in haematopoietic, osteo-adipogenic and neural progenitor cells. Among its diverse activities, ZNF521 has been implicated in the regulation of medulloblastoma (MB) cells, where the Hedgehog (HH) pathway, has a key role in the development of normal cerebellum and of a substantial fraction of MBs. Here a functional cross-talk is shown for ZNF521 with the HH pathway, where it interacts with GLI1 and GLI2, the major HH transcriptional effectors and enhances the activity of HH signalling. In particular, ZNF521 cooperates with GLI1 and GLI2 in the transcriptional activation of GLI (glioma-associated transcription factor)-responsive promoters. This synergism is dependent on the presence of the N-terminal, NuRD-binding motif in ZNF521, and is sensitive to HDAC (histone deacetylase) and GLI inhibitors. Taken together, these results highlight the role of ZNF521, and its interaction with the NuRD complex, in determining the HH response at the level of transcription. This may be of particular relevance in HH-driven diseases, especially regarding the MBs belonging to the SHH (sonic HH) subgroup where a high expression of ZNF521 is correlated with that of HH pathway components.

Abstract 3139: The microRNA 17-92 Cluster Mediates Sonic Hedgehog-driven Neurogenesis In Ischemic Neural Progenitor Cells

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Xianshuang Liu ◽  
Michael Chopp ◽  
Tao Tang ◽  
Haifa Kassis ◽  
Jennifer Xu ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Sonic Hedgehog ◽  
Functional Role ◽  
Neural Progenitor Cells ◽  
Neural Progenitor ◽  
Control Group ◽  
Western Blots ◽  
Shh Pathway ◽  
Empty Vector

Background: The Sonic hedgehog (Shh) pathway regulates stroke-induced neurogenesis. The present study investigated the functional role of the microRNA 17-92 (miR17-92) cluster in this process. Methods and Results: Analysis of miRNA microarray and real-time RT-PCR revealed that stroke substantially increased levels of individual members of the miR17-92 cluster: miR-18a (1.8±0.3), miR-19a (2.5±0.4), and miR-92a (1.9±0.3) expression in neural progenitor cells (NPCs) harvested from the subventricular zone (SVZ) of ischemic rats (n=6). Overexpression of the miR17-92 cluster in cultured NPCs significantly increased NPC proliferation measured by the number of BrdU positive cells (52±4% vs 28±2% in empty vector, n=3/group, p<0.05). Concurrently, overexpression of the miR17-92 cluster reduced PTEN (phosphatase and tensin homolog), a target of the miR17-92 cluster, protein levels by 70% compared to levels in NPCs transfected with an empty vector. PTEN suppresses cell proliferation. These data suggest that the stroke-upregulated miR17-92 cluster enhances NPC proliferation via downregulation of PTEN. To examine whether Shh regulates miR17-92 cluster expression, NPCs were incubated with recombinant human Shh (rhShh, 100ng/ml). We found that rhShh significantly (p<0.05) increased levels of individual members of the miR17-92 cluster: miR-18a (2.1±0.1), miR-19a (1.3±0.7), miR-19b (1.5±0.6) and miR-92a (1.9±0.8). Blockage of a Shh receptor Smo with cyclopamine suppressed rhShh-increased levels of miR-18a (0.9±0.08), miR-19a (0.7±0.01), miR-19b (0.6±0.05) and miR-92a (0.8±0.04). Attenuation of endogenous Shh in NPCs with siRNA also substantially decreased levels of miR-18a (0.6±0.1), miR-19a (0.4±0.05) and miR-92a (0.6±0.1) compared with levels in NPCs transfected with scrambled siRNA (1.0±0.2, n=3), indicating that Shh regulates miR17-92 expression. MYC is a downstream target of Shh. Western blots showed that stroke increased the protein level of N-MYC 1.8 fold in SVZ tissues and incubation of NPCs with rhShh elevated N-MYC levels by 1.8 fold, which was abrogated by cyclopamine (1.3 fold). N-MYC transduction resulted in significant increases in expression of the primary miR17-92 cluster (2.1±0.3 vs 1.0±0.2 in control group, n=3, p<0.05). These data suggest that the Shh pathway recruits N-MYC to regulate miR17-92 cluster expression in NPCs. Conclusion: Our data suggest a functional role of the miR17-92 cluster in mediating stroke-induced neurogenesis by the SHH/MYC signaling pathway, which provides new insight into molecular mechanisms of stroke-induced neurogenesis.

Haploinsufficiency of the forkhead geneFoxf1, a target for sonic hedgehog signaling, causes lung and foregut malformations

Development ◽  
2001 ◽  
Vol 128 (12) ◽  
pp. 2397-2406 ◽  
Author(s):  
Margit Mahlapuu ◽  
Sven Enerbäck ◽  
Peter Carlsson
Keyword(s):  
Sonic Hedgehog ◽  
Transcriptional Activation ◽  
Hedgehog Signaling ◽  
Gene Encoding ◽  
Sonic Hedgehog Signaling ◽  
Winged Helix ◽  
Morphogenetic Protein ◽  
Winged Helix Transcription Factor ◽  
Lung Lobes

The murine Foxf1 gene, encoding a forkhead – or winged helix – transcription factor, is expressed in splanchnic mesenchyme during organogenesis. The concentration of expression to subepithelial mesenchyme suggested that Foxf1 is activated by paracrine signals from endodermal epithelia. Homozygous Foxf1-null mice die before embryonic day 10, owing to defects in extra-embryonic mesoderm, and do not provide any information about the role of Foxf1 in morphogenesis of endodermally derived organs. We show that, on CD1 genetic background, Foxf1 heterozygote perinatal mortality is around 90%. The haploinsufficiency causes a variable phenotype that includes lung immaturity and hypoplasia, fusion of right lung lobes, narrowing of esophagus and trachea, esophageal atresia and tracheo-esophageal fistula. Similar malformations are observed in mutants that are defective in the sonic hedgehog (Shh) signaling pathway, and we show that exogenous Shh activates transcription of Foxf1 in developing lung. Foxf1 mRNA is absent in the lungs, foregut and sclerotomes of Shh−/− embryos, but persists in tissues where indian hedgehog (Ihh) is expressed. In lung organ cultures, activation of Foxf1 by Shh is counteracted by bone morphogenetic protein 4 (BMP4). Fibroblast growth factor (FGF) 10 and FGF7 both decrease Foxf1 expression and we speculate that this is mediated by transcriptional activation of epithelial Bmp4 (in the case of FGF10) and by inhibition of Shh expression for FGF7.

scholarly journals 18 – Role of Sonic Hedgehog Pathway in the Pathogenesis of Chronic Pancreatitis in Mouse Model

2019 ◽  
Vol 156 (6) ◽  
pp. S-7-S-8
Author(s):  
Mohammad Tarique ◽  
Hassam Cheema ◽  
Urvashi Hooda ◽  
Srikanth Iyer ◽  
Ejas Palathingal Bava ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Mouse Model ◽  
Sonic Hedgehog ◽  
Hedgehog Pathway ◽  
Sonic Hedgehog Pathway
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