Sphingosine-1-phosphate receptor inhibition prevents denervation-induced dendritic atrophy

Willems, Laurent M.; Zahn, Nadine; Ferreiròs, Nerea; Scholich, Klaus; Maggio, Nicola; Deller, Thomas; Vlachos, Andreas

doi:10.1186/s40478-016-0303-x

Cited by 12 publications

(11 citation statements)

References 58 publications

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“…OLIG2 is a neural stem cell transcription factor that regulates differentiation of oligodendrocytes (Zhou and Anderson 2002). S1PR1 and S1PR3 are involved in dendritic remodeling (Willems, et al 2016). Since these genes were also frequently co-up-regulated with ELL2 in the neuroendocrine prostate cancer dataset (see Figure 8A), ELL2 may play a role in the differentiation and proliferation of neuroendocrine cells through the regulation of RTN4, OLIG2, S1PR1 and S1PR3.…”

Section: Discussionmentioning

confidence: 99%

Conditional deletion of ELL2 induces murine prostate intraepithelial neoplasia

Pascal

Masoodi

Liu

et al. 2017

Journal of Endocrinology

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Elongation factor, RNA polymerase II, 2 (ELL2) is an RNA Pol II elongation factor with functional properties similar to ELL that can interact with the prostate tumor suppressor EAF2. In the prostate, ELL2 is an androgen response gene that is up-regulated in benign prostatic hyperplasia (BPH). We recently showed that ELL2 loss could enhance prostate cancer cell proliferation and migration, and that ELL2 gene expression was down-regulated in high Gleason score prostate cancer specimens. Here, prostate-specific deletion of ELL2 in a mouse model revealed a potential role for ELL2 as a prostate tumor suppressor in vivo. Ell2 knockout mice exhibited prostatic defects including increased epithelial proliferation, vascularity and PIN lesions similar to the previously determined prostate phenotype in Eaf2 knockout mice. Microarray analysis of prostates from Ell2 knockout and wild-type mice on a C57BL/6J background at age 3 mos and qPCR validation at 17 mos of age revealed a number of differentially expressed genes associated with proliferation, cellular motility and epithelial and neural differentiation. OncoPrint analysis identified combined down-regulation or deletion in prostate adenocarcinoma cases from the Cancer Genome Atlas (TCGA) data portal. These results suggest that ELL2 and its pathway genes likely play an important role in the development and progression of prostate cancer.

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Section: Discussionmentioning

confidence: 99%

Conditional deletion of ELL2 induces murine prostate intraepithelial neoplasia

Pascal

Masoodi

Liu

et al. 2017

Journal of Endocrinology

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“…While PAR1-mRNA was robustly detected in all layers of the DG in our preparations, no significant changes in PAR1-mRNA levels were observed following entorhinal denervation in vitro (Figure 4B ; a slight, but not significant increase was seen in the GCL during the early phase after denervation; Kruskal-Wallis-test following Dunn’s post hoc -test; p = 0.46). The results of these experiments disclosed that the loss of axonal input does not trigger major changes in PAR1-expression in the denervated DG of hippocampal slice cultures (c.f., Becker et al, 2013 , 2015 ; on increased mRNA-levels of tumor necrosis factor and its receptors after denervation; Willems et al, 2016 on increased sphingosine-phosphate-receptor mRNA).…”

Section: Resultsmentioning

confidence: 99%

“…This dendritic homeostasis is challenged by entorhinal denervation in vitro . As a consequence dendritic remodeling increases substantially, leading to a net reduction in TDL (see also Willems et al, 2016 ). Denervated neurons may eventually reach a new stable dynamic state at a later time point after the lesion (Caceres and Steward, 1983 ; Vuksic et al, 2011 ).…”

Section: Discussionmentioning

confidence: 99%

“…Sample sizes were chosen according to initial pilot experiments and prior studies that used similar experimental approaches to detect changes in dendritic morphologies/dynamics, spine densities, mEPSC properties and mRNA levels (e.g., Vlachos et al, 2009 ; Becker et al, 2013 ; Willems et al, 2016 ). Data were analyzed using GraphPad Prism 6 (GraphPad Software).…”

Section: Methodsmentioning

confidence: 99%

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Inhibition of Protease-Activated Receptor 1 Does not Affect Dendritic Homeostasis of Cultured Mouse Dentate Granule Cells

et al. 2016

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Protease-activated receptors (PARs) are widely expressed in the central nervous system (CNS). While a firm link between PAR1-activation and functional synaptic and intrinsic neuronal properties exists, studies on the role of PAR1 in neural structural plasticity are scarce. The physiological function of PAR1 in the brain remains not well understood. We here sought to determine whether prolonged pharmacologic PAR1-inhibition affects dendritic morphologies of hippocampal neurons. To address this question we employed live-cell microscopy of mouse dentate granule cell dendrites in 3-week old entorhino-hippocampal slice cultures prepared from Thy1-GFP mice. A subset of cultures were treated with the PAR1-inhibitor SCH79797 (1 μM; up to 3 weeks). No major effects of PAR1-inhibition on static and dynamic parameters of dentate granule cell dendrites were detected under control conditions. Granule cells of PAR1-deficient slice cultures showed unaltered dendritic morphologies, dendritic spine densities and excitatory synaptic strength. Furthermore, we report that PAR1-inhibition does not prevent dendritic retraction following partial deafferentation in vitro. Consistent with this finding, no major changes in PAR1-mRNA levels were detected in the denervated dentate gyrus (DG). We conclude that neural PAR1 is not involved in regulating the steady-state dynamics or deafferentation-induced adaptive changes of cultured dentate granule cell dendrites. These results indicate that drugs targeting neural PAR1-signals may not affect the stability and structural integrity of neuronal networks in healthy brain regions.

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“…The role of coagulation factors in the brain has only started to be unrevealed. Thrombin in the brain is implicated in synaptic plasticity and learning and memory [ 45 – 49 ], yet upregulation of thrombin in the brain has been linked to seizures [ 46 , 47 , 50 ], maladaptive synaptic plasticity [ 49 , 51 ], and brain death [ 52 ]. How neuroinflammation and brain coagulation interact among themselves is currently unknown.…”

Section: Discussionmentioning

confidence: 99%

Thrombin Inhibition Reduces the Expression of Brain Inflammation Markers upon Systemic LPS Treatment

et al. 2018

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Systemic inflammation and brain pathologies are known to be linked. In the periphery, the inflammation and coagulation systems are simultaneously activated upon diseases and infections. Whether this well-established interrelation also counts for neuroinflammation and coagulation factor expression in the brain is still an open question. Our aim was to study whether the interrelationship between coagulation and inflammation factors may occur in the brain in the setting of systemic inflammation. The results indicate that systemic injections of lipopolysaccharide (LPS) upregulate the expression of both inflammatory and coagulation factors in the brain. The activity of the central coagulation factor thrombin was tested by a fluorescent method and found to be significantly elevated in the hippocampus following systemic LPS injection (0.5 ± 0.15 mU/mg versus 0.2 ± 0.03 mU/mg in the control). A panel of coagulation factors and effectors (such as thrombin, FX, PAR1, EPCR, and PC) was tested in the hippocampus, isolated microglia, and N9 microglia cell by Western blot and real-time PCR and found to be modulated by LPS. One central finding is a significant increase in FX expression level following LPS induction both in vivo in the hippocampus and in vitro in N9 microglia cell line (5.5 ± 0.6- and 2.3 ± 0.1-fold of increase, resp.). Surprisingly, inhibition of thrombin activity (by a specific inhibitor NAPAP) immediately after LPS injection results in a reduction of both the inflammatory (TNFα, CXL9, and CCL1; p < 0.006) and coagulation responses (FX and PAR1; p < 0.004) in the brain. We believe that these results may have a profound clinical impact as they might indicate that reducing coagulation activity in the setting of neurological diseases involving neuroinflammation may improve disease outcome and survival.

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Sphingosine-1-phosphate receptor inhibition prevents denervation-induced dendritic atrophy

Cited by 12 publications

References 58 publications

Conditional deletion of ELL2 induces murine prostate intraepithelial neoplasia

Conditional deletion of ELL2 induces murine prostate intraepithelial neoplasia

Inhibition of Protease-Activated Receptor 1 Does not Affect Dendritic Homeostasis of Cultured Mouse Dentate Granule Cells

Thrombin Inhibition Reduces the Expression of Brain Inflammation Markers upon Systemic LPS Treatment

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