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Postembryonic neuronal addition in zebrafish dorsal root ganglia is regulated by Notch signaling.

ABSTRACT: BACKGROUND:The sensory neurons and glia of the dorsal root ganglia (DRG) arise from neural crest cells in the developing vertebrate embryo. In mouse and chick, DRG formation is completed during embryogenesis. In contrast, zebrafish continue to add neurons and glia to the DRG into adulthood, long after neural crest migration is complete. The molecular and cellular regulation of late DRG growth in the zebrafish remains to be characterized. RESULTS:In the present study, we use transgenic zebrafish lines to examine neuronal addition during postembryonic DRG growth. Neuronal addition is continuous over the period of larval development. Fate-mapping experiments support the hypothesis that new neurons are added from a population of resident, neural crest-derived progenitor cells. Conditional inhibition of Notch signaling was used to assess the role of this signaling pathway in neuronal addition. An increase in the number of DRG neurons is seen when Notch signaling is inhibited during both early and late larval development. CONCLUSIONS:Postembryonic growth of the zebrafish DRG comes about, in part, by addition of new neurons from a resident progenitor population, a process regulated by Notch signaling.

SUBMITTER: McGraw HF

PROVIDER: S-EPMC3438120 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Postembryonic neuronal addition in zebrafish dorsal root ganglia is regulated by Notch signaling.

McGraw Hillary Faye HF Snelson Corey D CD Prendergast Andrew A Suli Arminda A Raible David W DW

Neural development 20120627

<h4>Background</h4>The sensory neurons and glia of the dorsal root ganglia (DRG) arise from neural crest cells in the developing vertebrate embryo. In mouse and chick, DRG formation is completed during embryogenesis. In contrast, zebrafish continue to add neurons and glia to the DRG into adulthood, long after neural crest migration is complete. The molecular and cellular regulation of late DRG growth in the zebrafish remains to be characterized.<h4>Results</h4>In the present study, we use transg ...[more]

PMID: 22738203

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Project description:BackgroundWe aimed to explore activation of the Notch signaling pathway in knee-innervating lumbar dorsal root ganglia (DRG) in the course of experimental osteoarthritis (OA) in mice, and its role in knee hyperalgesia.MethodsCultured DRG cells were stimulated with the TLR4 agonist, lipopolysaccharide (LPS). Notch signaling in the cells was either inhibited with the γ-secretase inhibitor, DAPT, or with soluble Jagged1, or activated through immobilized Jagged1. CCL2 production was analyzed at mRNA and protein levels. In in vivo experiments, knee hyperalgesia was induced in naïve mice through intra-articular (IA) injection of LPS. The effect of inhibiting Notch signaling was examined by pre-injecting DAPT one hour before LPS. OA was induced through surgical destabilization of the medial meniscus (DMM) in male C57BL/6 mice. Gene expression in DRG was analyzed by qRT-PCR and RNAscope in situ hybridization. Activated Notch protein (NICD) expression in DRG was evaluated by ELISA and immunofluorescence staining. DAPT was injected IA 12 weeks post DMM to inhibit Notch signaling, followed by assessing knee hyperalgesia and CCL2 expression in the DRG.ResultsIn DRG cell cultures, LPS increased NICD in neuronal cells. Inhibition of Notch signaling with either DAPT or soluble Jagged1 attenuated LPS-induced increases of Ccl2 mRNA and CCL2 protein. Conversely, activating Notch signaling with immobilized Jagged1 enhanced these LPS effects. In vivo, IA injection of LPS increased expression of Notch genes and NICD in the DRG. Pre-injection of DAPT prior to LPS alleviated LPS-induced knee hyperalgesia, and decreased LPS-induced CCL2 expression in the DRG. Notch signaling genes were differentially expressed in the DRG from late-stage experimental OA. Notch1, Hes1, and NICD were increased in the neuronal cell bodies in DRG after DMM surgery. IA administration of DAPT alleviated knee hyperalgesia post DMM, and decreased CCL2 expression in the DRG.ConclusionsThese findings suggest a synergistic effect of Notch signaling with TLR4 in promoting CCL2 production and mediating knee hyperalgesia. Notch signaling is activated in knee-innervating lumbar DRG in mice with experimental OA, and is involved in mediating knee hyperalgesia. The pathway may therefore be explored as a target for alleviating OA pain.

Dataset Information

Postembryonic neuronal addition in zebrafish dorsal root ganglia is regulated by Notch signaling.

Publications

Postembryonic neuronal addition in zebrafish dorsal root ganglia is regulated by Notch signaling.

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