Microglia instruct subventricular zone neurogenesis

Walton, Noah M.; Sutter, Benjamin M.; Laywell, Eric D.; Levkoff, Lindsay H.; Kearns, Sean M.; Marshall, Gregory P.; Scheffler, Björn; Steindler, Dennis A.

doi:10.1002/glia.20419

Cited by 348 publications

(278 citation statements)

References 33 publications

Supporting

Mentioning

269

Contrasting

Unclassified

Order By: Relevance

“…We found that the IGF-1 receptor antagonist AG1024 effectively blocked SE-induced MAPK activation and attenuated progenitor cell proliferation. These observations are consistent with recent studies indicating an instructive role for microglia in SGZ cell proliferation and neurogenesis (Aarum et al, 2003;Battista et al, 2006;Walton et al, 2006;Yan et al, 2006). With respect to IGF-1, a number of studies have shown that circulating levels of IGF-1 stimulate proliferation (Aberg et al, 2000;Trejo et al, 2001).…”

Section: Discussionsupporting

confidence: 91%

“…Finally, in cell culture assays, the effects of IGF-1 on hippocampal progenitor cell proliferation were shown to be mediated, in part, via the MAPK pathway (Aberg et al, 2003). These findings, coupled with work implicating other trophic factors (Battista et al, 2006;Walton et al, 2006) suggest that IGF-1 is one key regulator of SE-induced progenitor cell proliferation.…”

Section: Discussionmentioning

confidence: 87%

See 1 more Smart Citation

IGF‐1 receptor‐mediated ERK/MAPK signaling couples status epilepticus to progenitor cell proliferation in the subgranular layer of the dentate gyrus

Choi

Cho

Hoyt

et al. 2008

Glia

133

View full text Add to dashboard Cite

Adult progenitor cell proliferation in the subgranular zone (SGZ) of the dentate gyrus is a dynamic process that is modulated by an array of physiological process, including locomotor activity and novel environmental stimuli. In addition, pathophysiological events, such as ischemia and status epilepticus (SE), have been shown to stimulate neurogenesis. Currently, limited information is available regarding the extracellular stimuli, receptors, and downstream intracellular effectors that couple excitotoxic stimulation to progenitor cell proliferation. Here we show that pilocarpineinduced SE triggers a set of signaling events that impinge upon the p42/44 mitogen-activated protein kinase (MAPK) pathway to drive progenitor cell proliferation in the SGZ at 2-days post-SE. Increased proliferation was dependent on insulin-like growth factor-1 (IGF-1), which was localized to activated microglia near the SGZ. Using a combination of techniques, we show that IGF-1 is a CREB-regulated gene and that SE triggered CRE-dependent transcription in microglia at 2-days post-SE. Together, these data identify a potential signaling program that couples SE to progenitor cell proliferation. SE triggers CREB-dependent transcription in reactive microglia. As a CREB-target gene, IGF-1 expression is upregulated, and by 2-days post-SE, IGF-1 triggers MAPK pathway activation in progenitor cells and, in turn, an increase in progenitor cell proliferation.

show abstract

Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 87%

IGF‐1 receptor‐mediated ERK/MAPK signaling couples status epilepticus to progenitor cell proliferation in the subgranular layer of the dentate gyrus

Choi

Cho

Hoyt

et al. 2008

Glia

133

View full text Add to dashboard Cite

show abstract

“…However, in the past decade neuroimmune crosstalk-direct interplay between neuronal and immune cells-has been shown to be critical for neurodevelopment (54), synaptic homeostasis (55), and adultstage neurogenesis (56) and may play beneficial roles during neurodegenerative disease (24,28). For instance, acute activation of microglia may function to protect neurons from accumulations of cytotoxic derivatives of dying cells and stress-related signaling pathways during the early stages of neurodegeneration.…”

Section: Discussionmentioning

confidence: 99%

Immunomodulation-accelerated neuronal regeneration following selective rod photoreceptor cell ablation in the zebrafish retina

White¹,

Sengupta²,

Saxena³

et al. 2017

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

159

218

View full text Add to dashboard Cite

Müller glia (MG) function as inducible retinal stem cells in zebrafish, completely repairing the eye after damage. The innate immune system has recently been shown to promote tissue regeneration in which classic wound-healing responses predominate. However, regulatory roles for leukocytes during cellular regeneration-i.e., selective cell-loss paradigms akin to degenerative disease-are less well defined. To investigate possible roles innate immune cells play during retinal cell regeneration, we used intravital microscopy to visualize neutrophil, macrophage, and retinal microglia responses to induced rod photoreceptor apoptosis. Neutrophils displayed no reactivity to rod cell loss. Peripheral macrophage cells responded to rod cell loss, as evidenced by morphological transitions and increased migration, but did not enter the retina. Retinal microglia displayed multiple hallmarks of immune cell activation: increased migration, translocation to the photoreceptor cell layer, proliferation, and phagocytosis of dying cells. To test function during rod cell regeneration, we coablated microglia and rod cells or applied immune suppression and quantified the kinetics of (i) rod cell clearance, (ii) MG/progenitor cell proliferation, and (iii) rod cell replacement. Coablation and immune suppressants applied before cell loss caused delays in MG/progenitor proliferation rates and slowed the rate of rod cell replacement. Conversely, immune suppressants applied after cell loss had been initiated led to accelerated photoreceptor regeneration kinetics, possibly by promoting rapid resolution of an acute immune response. Our findings suggest that microglia control MG responsiveness to photoreceptor loss and support the development of immune-targeted therapeutic strategies for reversing cell loss associated with degenerative retinal conditions. retina | microglia | glucocorticoid | regeneration | macrophage N eurodegenerative diseases are caused by the loss of discrete neuronal cell types. The goal of regenerative medicine is to reverse this process. One strategy for doing so involves harnessing the regenerative potential of endogenous neural stem cells. Unfortunately, although adult neural stem cells exist in the mammalian CNS, innate potentials for neuronal repair remain dormant in the absence of exogenous stimulation. Conversely, many other species are endowed with remarkable capacities for neuronal regeneration. For instance, in the zebrafish eye, retinal Müller glia (MG) cells can dedifferentiate to a stem cell-like state and give rise to progenitors that replace lost neurons and restore visual function (1, 2). Intriguingly, human MG cells are able to give rise to new neurons in culture (3) that can restore visual function when transplanted into mammalian disease models (4), suggesting that human MG retain a stem cell-like capacity for mediating retinal repair. Mechanisms controlling the regenerative potential of MG are therefore of great interest. We and others study zebrafish to learn more about how retinal regeneration is cont...

show abstract

“…Previous in vivo studies attempting to elucidate the role of microglia and their activation status in adult neurogenesis have been mostly correlative, examining, for example, microglia numbers under various experimental conditions but not directly demonstrating a specific role for these cells in the regulation of NPC activity and neurogenesis (Ekdahl et al, 2003;Monje et al, 2003;Ziv et al, 2006;Olah et al, 2009). Additional in vitro studies have yielded generalized insights regarding how microglia could differentially influence adult neurogenesis (Walton et al, 2006;Deierborg et al, 2010), with Walton et al (2006) being the first to suggest that a soluble factor found in the microglia-conditioned medium could rescue the ability of extensively passaged SVZ neural precursors to differentiate into immature neurons. Other studies have assessed neurogenesis in response to artificial stimulation with lipopolysaccharide or cytokines (Aarum et al, 2003;Deierborg et al, 2010).…”

Section: Role Of Microglia In Neural Precursor Activationmentioning

confidence: 99%

“…Proinflammatory microglia are generally associated with reduced neurogenesis, as in this state they produce reactive oxygen species and nitric oxide, and release proinflammatory cytokines (Monje et al, 2003;Nakanishi et al, 2007). Conversely, neuroprotective microglia stimulate neurogenesis through the release of antiinflammatory cytokines and growth factors (Aarum et al, 2003;Morgan et al, 2004;Battista et al, 2006;Butovsky et al, 2006;Walton et al, 2006;Ziv et al, 2006;Deierborg et al, 2010). However, the cellular and molecular pathways that mediate the positive effects of voluntary exercise are largely unknown, and whether exercise-induced microglial proliferation and/or altered activation status contribute to increased NPC activity also remains unclear (Vukovic et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Microglia Modulate Hippocampal Neural Precursor Activity in Response to Exercise and Aging

Vukovic¹,

Colditz²,

Blackmore³

et al. 2012

J. Neurosci.

206

184

View full text Add to dashboard Cite

Exercise has been shown to positively augment adult hippocampal neurogenesis; however, the cellular and molecular pathways mediating this effect remain largely unknown. Previous studies have suggested that microglia may have the ability to differentially instruct neurogenesis in the adult brain. Here, we used transgenic Csf1r-GFP mice to investigate whether hippocampal microglia directly influence the activation of neural precursor cells. Our results revealed that an exercise-induced increase in neural precursor cell activity was mediated via endogenous microglia and abolished when these cells were selectively removed from hippocampal cultures. Conversely, microglia from the hippocampi of animals that had exercised were able to activate latent neural precursor cells when added to neurosphere preparations from sedentary mice. We also investigated the role of CX 3 CL1, a chemokine that is known to provide a more neuroprotective microglial phenotype. Intraparenchymal infusion of a blockingantibodyagainsttheCX 3 CL1receptor,CX 3 CR1,butnotcontrolIgG,dramaticallyreducedtheneurosphereformationfrequencyinmice thathadexercised.WhileanincreaseinsolubleCX 3 CL1wasobservedfollowingrunning,reducedlevelsofthischemokinewerefoundintheaged brain.LowerlevelsofCX 3 CL1withadvancingagecorrelatedwiththenaturaldeclineinneuralprecursorcellactivity,astatethatcouldbepartially alleviated through removal of microglia. These findings provide the first direct evidence that endogenous microglia can exert a dual and opposing influence on neural precursor cell activity within the hippocampus, and that signaling through the CX 3 CL1-CX 3 CR1 axis critically contributes toward this process.

show abstract

Microglia instruct subventricular zone neurogenesis

Cited by 348 publications

References 33 publications

IGF‐1 receptor‐mediated ERK/MAPK signaling couples status epilepticus to progenitor cell proliferation in the subgranular layer of the dentate gyrus

IGF‐1 receptor‐mediated ERK/MAPK signaling couples status epilepticus to progenitor cell proliferation in the subgranular layer of the dentate gyrus

Immunomodulation-accelerated neuronal regeneration following selective rod photoreceptor cell ablation in the zebrafish retina

Microglia Modulate Hippocampal Neural Precursor Activity in Response to Exercise and Aging

Contact Info

Product

Resources

About