Dataset Information

Identification of miRNAs involved in DRG neurite outgrowth and their putative targets.

ABSTRACT: Peripheral neurons regenerate their axons after injury. Transcriptional regulation by microRNAs (miRNAs) is one possible mechanism controlling regeneration. We profiled miRNA expression in mouse dorsal root ganglion neurons after a sciatic nerve crush, and identified 49 differentially expressed miRNAs. We evaluated the functional role of each miRNA using a phenotypic analysis approach. To predict the targets of the miRNAs we employed RNA-Sequencing and examined transcription at the isoform level. We identify thousands of differentially expressed isoforms and bioinformatically associate the miRNAs that modulate neurite growth with their putative target isoforms to outline a network of regulatory events underlying peripheral nerve regeneration. MiR-298, let-7a, and let-7f enhance neurite growth and target the majority of isoforms in the differentially expressed network.

SUBMITTER: Motti D

PROVIDER: S-EPMC5864114 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Identification of miRNAs involved in DRG neurite outgrowth and their putative targets.

Motti Dario D Lerch Jessica K JK Danzi Matt C MC Gans Jared H JH Kuo Frank F Slepak Tatiana I TI Bixby John L JL Lemmon Vance P VP

FEBS letters 20170702 14

Peripheral neurons regenerate their axons after injury. Transcriptional regulation by microRNAs (miRNAs) is one possible mechanism controlling regeneration. We profiled miRNA expression in mouse dorsal root ganglion neurons after a sciatic nerve crush, and identified 49 differentially expressed miRNAs. We evaluated the functional role of each miRNA using a phenotypic analysis approach. To predict the targets of the miRNAs we employed RNA-Sequencing and examined transcription at the isoform level ...[more]

PMID: 28626869

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Project description:Peripheral sensory neurons in the dorsal root ganglia (DRG) are the initial transducers of sensory stimuli, including painful stimuli, from the periphery to central sensory and pain-processing centers. Small- to medium-diameter non-peptidergic neurons in the neonatal DRG express functional kainate receptors (KARs), one of three subfamilies of ionotropic glutamate receptors, as well as the putative KAR auxiliary subunit Neuropilin- and tolloid-like 2 (Neto2). Neto2 alters recombinant KAR function markedly but has yet to be confirmed as an auxiliary subunit that assembles with and alters the function of endogenous KARs. KARs in neonatal DRG require the GluK1 subunit as a necessary constituent, but it is unclear to what extent other KAR subunits contribute to the function and proposed roles of KARs in sensory ganglia, which include promotion of neurite outgrowth and modulation of glutamate release at the DRG-dorsal horn synapse. In addition, KARs containing the GluK1 subunit are implicated in modes of persistent but not acute pain signaling. We show here that the Neto2 protein is highly expressed in neonatal DRG and modifies KAR gating in DRG neurons in a developmentally regulated fashion in mice. Although normally at very low levels in adult DRG neurons, Neto2 protein expression can be upregulated via MEK/ERK signaling and after sciatic nerve crush and Neto2-/- neurons from adult mice have stunted neurite outgrowth. These data confirm that Neto2 is a bona fide KAR auxiliary subunit that is an important constituent of KARs early in sensory neuron development and suggest that Neto2 assembly is critical to KAR modulation of DRG neuron process outgrowth.SIGNIFICANCE STATEMENT Pain-transducing peripheral sensory neurons of the dorsal root ganglia (DRG) express kainate receptors (KARs), a subfamily of glutamate receptors that modulate neurite outgrowth and regulate glutamate release at the DRG-dorsal horn synapse. The putative KAR auxiliary subunit Neuropilin- and tolloid-like 2 (Neto2) is also expressed in DRG. We show here that it is a developmentally downregulated but dynamic component of KARs in these neurons, that it contributes to regulated neurite regrowth in adult neurons, and that it is increased in adult mice after nerve injury. Our data confirm Neto2 as a KAR auxiliary subunit and expand our knowledge of the molecular composition of KARs in nociceptive neurons, a key piece in understanding the mechanistic contribution of KAR signaling to pain-processing circuits.

Dataset Information

Identification of miRNAs involved in DRG neurite outgrowth and their putative targets.

Publications

Identification of miRNAs involved in DRG neurite outgrowth and their putative targets.

Similar Datasets

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