TNFa/TNFR2 signaling is required for glial ensheathment at the dorsal root entry zone

Smith, Cody J.; Wheeler, Michael A.; Marjoram, Lindsay; Bagnat, Michel; Deppmann, Christopher D.; Kucenas, Sarah

doi:10.1371/journal.pgen.1006712

Cited by 18 publications

(18 citation statements)

References 46 publications

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“…1a) 11 . Between 48 and 72 hpf, zebrafish dorsal root ganglia pioneer axons initiate dorsally, navigate to the DREZ, and cross into the spinal cord 6,11 . The DREZ is established 18.075 ± 0.681 µm (mean ± SEM) from the DRG neuronal soma (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…To ensure sensory information is rapid and uninterrupted, glial cells and axons coordinate at the dorsal root entry zone (DREZ), the CNS/peripheral nervous system (PNS) interface where sensory axons establish their dual domain nature 4,5 . During development, these sensory axons of the dorsal root ganglia (DRG) traverse into the spinal cord and glial cells reorganize 6,7 . This strict organization of the nerve is essential to drive somatosensory-induced behavior.…”

Section: Introductionmentioning

confidence: 99%

“…Whether the battering ram is a distinct axonal structure or an overall term for the growth cone is unclear. Time-lapse imaging of pioneer axons shows that neural crest cells associate with the axons while they navigate to the DREZ, but the growth cone leads the neural crest cells 6 . In such imaging, however, the actual entry of the axons was not investigated.…”

Section: Introductionmentioning

confidence: 99%

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Pioneer axons employ Cajal’s battering ram to enter the spinal cord

Nichols

Smith

2019

Nat Commun

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Sensory axons must traverse a spinal cord glia limitans to connect the brain with the periphery. The fundamental mechanism of how these axons enter the spinal cord is still debatable; both Ramon y Cajal’s battering ram hypothesis and a boundary cap model have been proposed. To distinguish between these hypotheses, we visualized the entry of pioneer axons into the dorsal root entry zone (DREZ) with time-lapse imaging in zebrafish. Here, we identify that DRG pioneer axons enter the DREZ before the arrival of neural crest cells at the DREZ. Instead, actin-rich invadopodia in the pioneer axon are necessary and sufficient for DREZ entry. Using photoactivable Rac1, we demonstrate cell-autonomous functioning of invasive structures in pioneer axon spinal entry. Together these data support the model that actin-rich invasion structures dynamically drive pioneer axon entry into the spinal cord, indicating that distinct pioneer and secondary events occur at the DREZ.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pioneer axons employ Cajal’s battering ram to enter the spinal cord

Nichols

Smith

2019

Nat Commun

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“…TNF-α mediates a variety of cell-signaling processes involved in the immune response and carcinogenesis, primarily via its interaction with TNFR1 and/or TNFR2 (62,63). TNFR1 is a central regulator of signal transduction pathways whereas TNFR2 is expressed on a very narrow subset of immune cells (64)(65)(66). Based on our previous study on the effects of TNF-α on c-Jun/MACC1 signaling, we exposed CRC cells to blocking antibodies for TNFR1 or TNFR2, respectively.…”

Section: Discussionmentioning

confidence: 99%

Pro-inflammatory TNF-α and IFN-γ Promote Tumor Growth and Metastasis via Induction of MACC1

et al. 2020

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Colorectal cancer (CRC) is one of the most common malignancies worldwide. Early stage CRC patients have a good prognosis. If distant metastasis occurs, the 5-year survival drops below 10%. Despite treatment success over the last decades, treatment options for metastatic disease are still limited. Therefore, novel targets are needed to foster therapy of advanced stage CRC patients and hinder progression of early stage patients into metastasis. A novel target is the crucial oncogene Metastasis-Associated in Colon Cancer 1 (MACC1) involved in molecular pathogenesis of CRC metastasis. MACC1 induces cell proliferation and motility, supports cellular survival and rewires metabolism resulting in increased metastasis in vivo. MACC1 is a prognostic biomarker not only for CRC but for more than 20 solid cancer entities. Inflammation plays a pivotal role in tumorigenesis, tumor progression and metastasis. For CRC, inflammatory bowel disease and ulcerative colitis are important inflammation associated risk factors. Certain cytokines, such as TNF-α and IFN-γ, are key factors in determining the contribution of the inflammatory process to CRC. Knowledge of the connection between inflammation and MACC1 driven tumors remains unclear. Gene expression analysis of CRC cells after cytokine stimulation was analyzed by qRT-PCR and Western blot. Cellular motility was assessed by Boyden chamber assays. MACC1 promoter activity after stimulation with pro-inflammatory cytokines was measured using promoter-luciferase constructs. To investigate signal transduction from receptor to effector molecules, blocking experiments using neutralizing antibodies and knockdown experiments were performed. Following TNF-α stimulation, MACC1 and c-Jun expression were significantly increased at the mRNA and protein level. Knockdown of c-Jun reduced MACC1 inducibility following TNF-α stimulation. TNF-α promoted MACC1-induced cell migration that was reverted following MACC1 knockdown. Moreover, MACC1 and c-Jun expression were downregulated by blocking TNFR1, but not TNFR2. Knock down of the NF-κB subunit, p65, reduced basal MACC1 and c-Jun mRNA expression levels. Adalimumab, a clinically approved monoclonal anti-TNF-α antibody, hindered MACC1 induction. The present Kobelt et al. Inflammation-Induced MACC1 Expression study highlights that TNF-α regulates the induction of MACC1 via the NF-κB subunit p65 and the transcription factor c-Jun in CRC cells. This finding unravels a novel signaling pathway upstream of MACC1 and provides a potential therapeutic target for the treatment of CRC patients with an associated inflammation.

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“…Furthermore, as transmembrane TNF is predominantly on astrocytes, whereas transmembrane TNFR2 is expressed on neurons, the bidirectional signaling of transmembrane TNF and TNFR2 could be important in direct communication between these cell types. This notion is supported by the finding that ensheathment of some axons by associated glia is controlled by bidirectional signaling involving transmembrane TNF and TNFR2 …”

Section: Tnfr2: Structure Function and Possible Role In The Pathophymentioning

confidence: 83%

Tumor necrosis factor receptor 2: A potential target for antidepressant drug development

Seymour

Gibbons

Dean

2019

Clinical & Exp Neuroim

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A large body of work implicates cytokines and their related pathways in the pathophysiologies of mood disorders. Much of the data on the role of cytokines in major depression and bipolar disorder suggest that pathways regulated by tumor necrosis factor (TNF)‐α make a significant contribution to their pathophysiologies. In the present review, we contrast the well‐established role of TNF‐related pathways acting to mediate classic pro‐inflammatory cytokine activity with growing evidence that such pathways have more diverse functions in the human central nervous system. Here, it will be argued that changes in levels of the TNF receptor type 2 in mood disorders would be consistent with a neuroprotective role for the receptor against the pathophysiologies of mood disorders. This hypothesis is of significance when considering how interventions that act to modulate TNF‐regulated pathways can be used to treat the symptoms of mood disorders.

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TNFa/TNFR2 signaling is required for glial ensheathment at the dorsal root entry zone

Cited by 18 publications

References 46 publications

Pioneer axons employ Cajal’s battering ram to enter the spinal cord

Pioneer axons employ Cajal’s battering ram to enter the spinal cord

Pro-inflammatory TNF-α and IFN-γ Promote Tumor Growth and Metastasis via Induction of MACC1

Tumor necrosis factor receptor 2: A potential target for antidepressant drug development

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