Transient Maternal IL-6 Mediates Long-Lasting Changes in Neural Stem Cell Pools by Deregulating an Endogenous Self-Renewal Pathway

Gallagher, Denis; Norman, Andreea; Woodard, Cameron L.; Yang, Guang; Gauthier-Fisher, Andrée; Fujitani, Masashi; Vessey, John P.; Cancino, Gonzalo I.; Sachewsky, Nadia; Woltjen, Knut; Fatt, Michael P.; Morshead, Cindi M.; Kaplan, David R.; Miller, Freda D.

doi:10.1016/j.stem.2013.10.002

Cited by 76 publications

(81 citation statements)

References 34 publications

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“…Recent studies demonstrate that acute inflammation is required and sufficient to enhance proliferation of neural progenitors and subsequent neurogenesis after brain injury in zebrafish (23). In the embryonic stage, administration of IL-6 increases BrdU-labeled calretinin + neurons in the mouse olfactory bulb (24). These findings raise the possibility that inflammation directly contributes to the regulation of neurogenesis, with distinct consequences depending on the stage or intensity of the immune response.…”

mentioning

confidence: 97%

Acute inflammation regulates neuroregeneration through the NF-κB pathway in olfactory epithelium

Chen

Reed

Lane

2017

Proc. Natl. Acad. Sci. U.S.A.

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Adult neural stem cells/progenitor cells residing in the basal layer of the olfactory epithelium are capable of reconstituting the neuroepithelium even after severe damage. The molecular events underlying this regenerative capacity remain elusive. Here we show that the repair of neuroepithelium after lesioning is accompanied by an acute, but self-limited, inflammatory process. Attenuation of inflammatory cell recruitment and cytokine production by dexamethasone impairs proliferation of progenitor horizontal basal cells (HBCs) and subsequent neuronal differentiation. Using TNF-α receptor-deficient mice, we identify TNF-α signaling as an important contributor to this inflammatory and reparative process, mainly through TNF-α receptor 1. HBC-selective genetic ablation of RelA (p65), the transcriptional activator of the NF-κB pathway, retards inflammation and impedes proliferation at the early stages of regeneration and suggests HBCs directly participate in cross-talk between immune response and neurogenesis. Loss of RelA in the regenerating neuroepithelium perturbs the homeostasis between proliferation and apoptosis while enhancing JNK signaling. Together, our results support a model in which acute inflammation after injury initiates important regenerative signals in part through NF-κB-mediated signaling that activates neural stem cells to reconstitute the olfactory epithelium.neuroregeneration | inflammation | olfactory stem cells | NF-κB

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mentioning

confidence: 97%

Acute inflammation regulates neuroregeneration through the NF-κB pathway in olfactory epithelium

Chen

Reed

Lane

2017

Proc. Natl. Acad. Sci. U.S.A.

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“…In utero electroporations were performed on E14.5 mice using a square wave electroporator CUY21SC (NEPAGENE) that delivered five 50-ms pulses of 40 V with 950-ms intervals as described3233. We injected a mixture of a nuclear EGFP expression vector with MINP -siRNA (Invitrogen) at a ratio of 1:1.…”

Section: Methodsmentioning

confidence: 99%

The newly identified migration inhibitory protein regulates the radial migration in the developing neocortex

Zhang

Kanemitsu

Fujitani

et al. 2014

Sci Rep

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Neuronal migration is a crucial process in the organization of the developing cerebral cortex. Although a number of positive regulatory mechanisms of radial migration have been identified, negative cell-autonomous mechanisms have yet to be fully described. Here we report a newly identified Migration Inhibitory Protein (MINP, formerly known as 2900011O08Rik) that negatively regulates radial migration. MINP mRNA was specifically detected in the central and peripheral nervous system, and especially enriched in the cerebral cortex. MINP immunoreactivity co-localized with the neuronal marker Tuj1 and was detected in the cytoplasm of post-mitotic neurons. To elucidate the function of MINP in the developing brain, we performed in utero electroporation of MINP siRNA, MINP shRNA, or MINP-overexpressing vectors into mouse cortices and carried out in vivo migration assays. Whereas knockdown of MINP did not alter neuronal morphology, the radial migration was found accelerated by MINP knockdown, and reduced by MINP overexpression. This migration phenotype was also confirmed in vitro, indicating that MINP regulates neuronal migration in a cell-autonomous fashion. Furthermore, downregulation of MINP affected microtubule stability by interacting with tubulin that is a potential mechanism involved in the regulation of neuronal migration.

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“…Multiple lines of evidence support a critical non-immune role for the complement system and cytokines in both normal and abnormal neurodevelopmental processes (i.e. synaptic pruning, synaptic refinement, regulation of neural stem cell pools, neurodegenerative diseases) [13,48,49]. Maternal inflammation at the placental-fetal interface can induce an inflammatory response in the foetus.…”

Section: Mechanisms Of Impaired Neurodevelopment Following In Utero Ementioning

confidence: 99%

“…IL-6 is frequently induced during prenatal infections and has been detected at elevated levels in maternal serum, placenta, and fetal brain in the poly (I:C) model of maternal infection [51]. Mechanistically, IL-6 is critically involved in the regulation of neural stem cell pools and neurogenesis [48], and elevated levels can contribute to aberrations in these developmental processes, resulting in long term neurological deficits [51]. This contention is supported by the findings that functional blockade (e.g.…”

Section: Mechanisms Of Impaired Neurodevelopment Following In Utero Ementioning

confidence: 99%

Malaria in Pregnancy: An Unrecognized Risk Factor for Neuropsychiatric Disease in Offspring?

Tran¹,

Weckman²,

Kain

2016

Pediatric Infect Dis

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The in vitro environment has a profound effect on offspring neurodevelopment. Insults to the foetus during pregnancy can disrupt neurodevelopmental processes culminating in neurochemical and behavioural abnormalities. A growing body of evidence supports a role for maternal infection in precipitating neuropsychiatric disease in offspring. Sincẽ 60% of pregnancies globally are at risk of malaria infection annually, we hypothesize that in utero exposure to malaria in pregnancy (MIP) may be a neglected risk factor for mental illness. We propose that the host response to infection makes an important contribution to this risk. MIP may mediate neuropathology via immune activation and inflammation in the placenta and consequent dysregulation of processes critical to fetal neurodevelopment including cerebral angiogenesis, neurogenesis, synaptic pruning, and neurochemical regulation.

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Transient Maternal IL-6 Mediates Long-Lasting Changes in Neural Stem Cell Pools by Deregulating an Endogenous Self-Renewal Pathway

Cited by 76 publications

References 34 publications

Acute inflammation regulates neuroregeneration through the NF-κB pathway in olfactory epithelium

Acute inflammation regulates neuroregeneration through the NF-κB pathway in olfactory epithelium

The newly identified migration inhibitory protein regulates the radial migration in the developing neocortex

Malaria in Pregnancy: An Unrecognized Risk Factor for Neuropsychiatric Disease in Offspring?

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