Interferon Gamma and Sonic Hedgehog Signaling Are Required to Dysregulate Murine Neural Stem/Precursor Cells

Walter, Janine; Hartung, Hans‐Peter; Dihné, Marcel

doi:10.1371/journal.pone.0043338

Cited by 9 publications

(15 citation statements)

References 30 publications

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“…Mounting evidence suggests that IFNc can activate distinct signaling pathways and gene expression profiles in a cell type-specific manner, with subsequent effects on cell physiology, function, and survival (Huynh and Dorovini-Zis 1993;van Boxel-Dezaire and Stark 2007;Vidal et al 2012;Zhang et al 2013;Natarajan et al 2014). In neural cells of the CNS, a variety of IFNc signaling signatures are seen, often involving Jak/Stat1 activation in combination with other Stat family members, other transcription factors, or kinases (Burdeinick-Kerr and Griffin 2005;Kim et al 2007;Lin et al 2012;Walter et al 2012). Previous work from our laboratory has shown that primary hippocampal neurons express low basal levels of Stat1 in comparison to primary fibroblasts and astrocytes, leading to a delay in Stat1 activation and reduced expression of canonical Stat1-responsive genes in primary neurons (Rose et al 2007;O'Donnell et al 2012).…”

Section: Discussionmentioning

confidence: 99%

Interferon gamma induces protective non‐canonical signaling pathways in primary neurons

O’Donnell

Henkins

Kulkarni

et al. 2015

Journal of Neurochemistry

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The signal transduction molecule, Stat1, is critical for the expression of type I and II interferon (IFN)-responsive genes in most cells; however, we previously showed that primary hippocampal mouse neurons express low basal Stat1, with delayed and attenuated expression of IFN-responsive genes. Moreover, IFNγ-dependent resolution of a neurotropic viral challenge in permissive mice is Stat1-independent. Here, we show that exogenous INFγ has no deleterious impact on neuronal viability, and staurosporine-induced apoptosis in neurons is significantly blunted by the addition of INFγ, suggesting that INFγ confers a pro-survival signal in neurons. To identify the pathways induced by INFγ in neurons, the activation of alternative signal transducers associated with INFγ signaling was assessed. Rapid and pronounced activation of extracellular signal regulated kinase (Erk1/2) was observed in neurons, compared to a modest response in fibroblasts. Moreover, the absence of Stat1 in primary fibroblasts led to enhanced Erk activation following IFNγ addition, implying that the cell-specific availability of signal transducers can diversify the cellular response following IFN engagement.

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Section: Discussionmentioning

confidence: 99%

Interferon gamma induces protective non‐canonical signaling pathways in primary neurons

O’Donnell

Henkins

Kulkarni

et al. 2015

Journal of Neurochemistry

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“…First and foremost, the use of different types of cell culture, particularly human or animal cells, is an important aspect to be taken into consideration. Studies reviewed here provided evidence for divergent responses between human and animal cells after exposure to specific cytokines, including IL-1b [37,[39][40][41][42]49,50], IFN-g [67,76,77], and TNF-a [72,[79][80][81]. In fact, while these modulators induce a striking dysregulation in neuronal formation in animals, they have diverse effects in human NSCs [78,84].…”

Section: Factors Regulating the Effects Of Cytokines On Neurogenesismentioning

confidence: 92%

“…Of note, in one study, numerous cells coexpressed beta-III tubulin (b-III-tubulin) and the glial fibrillary acid protein (GFAP), but electrophysiological results showed that cells were functionally distinct from mature neurons as well as astrocytes, suggesting IFN-g as a promoter of the dysregulated NPC-derived cellular phenotype [76]. Results were replicated, confirming a phenotypic dysregulation (b-III-tubulin-GFAP co-expression) induced by IFN-g in rat fetal HYNPCs [77].…”

Section: Reviewmentioning

confidence: 95%

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The role of inflammatory cytokines as key modulators of neurogenesis

Borsini

Zunszain

Thuret

et al. 2015

Trends in Neurosciences

309

199

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Neurogenesis is an important process in the regulation of brain function and behaviour, highly active in early development and continuing throughout life. Recent studies have shown that neurogenesis is modulated by inflammatory cytokines in response to an activated immune system. To disentangle the effects of the different cytokines on neurogenesis, here we summarise and discuss in vitro studies on individual cytokines. We show that inflammatory cytokines have both a positive and negative role on proliferation and neuronal differentiation. Hence, this strengthens the notion that inflammation is involved in molecular and cellular mechanisms associated with complex cognitive processes and, therefore, that alterations in brain-immune communication are relevant to the development of neuropsychiatric disorders.

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“…The JAK-STAT pathway is canonically induced by IFNs [ 52 ], which are key mediators of astrogliogenesis in neural stem cells [ 53 ]. IFN γ treatment of proliferative wild-type murine E14 neurosphere-derived neural precursor cells showed reduced proliferation but upregulated GFAP and β III-tubulin expression with simultaneous sonic hedgehog and Stat1 activation [ 54 ]. Moreover, IFN β treatment of human SH-SY5Y cells and mouse primary cortical neurons was recently shown to negatively regulate brain-derived neurotrophic factor signaling and action via prevention of tropomyosin-related kinase receptor type B activation.…”

Section: Potential Roles Of Jak-stat Signaling In Promoting Gliogementioning

confidence: 99%

Potential Role of JAK-STAT Signaling Pathway in the Neurogenic-to-Gliogenic Shift in Down Syndrome Brain

et al. 2016

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Trisomy of human chromosome 21 in Down syndrome (DS) leads to several phenotypes, such as mild-to-severe intellectual disability, hypotonia, and craniofacial dysmorphisms. These are fundamental hallmarks of the disorder that affect the quality of life of most individuals with DS. Proper brain development involves meticulous regulation of various signaling pathways, and dysregulation may result in abnormal neurodevelopment. DS brain is characterized by an increased number of astrocytes with reduced number of neurons. In mouse models for DS, the pool of neural progenitor cells commits to glia rather than neuronal cell fate in the DS brain. However, the mechanism(s) and consequences of this slight neurogenic-to-gliogenic shift in DS brain are still poorly understood. To date, Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling has been proposed to be crucial in various developmental pathways, especially in promoting astrogliogenesis. Since both human and mouse models of DS brain exhibit less neurons and a higher percentage of cells with astrocytic phenotypes, understanding the role of JAK-STAT signaling in DS brain development will provide novel insight into its role in the pathogenesis of DS brain and may serve as a potential target for the development of effective therapy to improve DS cognition.

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Interferon Gamma and Sonic Hedgehog Signaling Are Required to Dysregulate Murine Neural Stem/Precursor Cells

Cited by 9 publications

References 30 publications

Interferon gamma induces protective non‐canonical signaling pathways in primary neurons

Interferon gamma induces protective non‐canonical signaling pathways in primary neurons

The role of inflammatory cytokines as key modulators of neurogenesis

Potential Role of JAK-STAT Signaling Pathway in the Neurogenic-to-Gliogenic Shift in Down Syndrome Brain

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