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Serum response factor mediates NGF-dependent target innervation by embryonic DRG sensory neurons.

ABSTRACT: Serum response factor (SRF) is a prototypic transcription factor that mediates stimulus-dependent gene expression. Here, we show that SRF mediates NGF signaling, axonal growth, branching, and target innervation by embryonic DRG sensory neurons. Conditional deletion of the murine SRF gene in DRGs results in no deficits in neuronal viability or differentiation but causes defects in extension and arborization of peripheral axonal projections in the target field in vivo, similar to the target innervation defects observed in mice lacking NGF. Moreover, SRF is both necessary and sufficient for NGF-dependent axonal outgrowth in vitro, and NGF regulates SRF-dependent gene expression and axonal outgrowth through activation of both MEK/ERK and MAL signaling pathways. These findings show that SRF is a major effector of both MEK/ERK and MAL signaling by NGF and that SRF is a key mediator of NGF-dependent target innervation by embryonic sensory neurons.

SUBMITTER: Wickramasinghe SR

PROVIDER: S-EPMC2689374 | biostudies-literature | 2008 May

REPOSITORIES: biostudies-literature

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Serum response factor mediates NGF-dependent target innervation by embryonic DRG sensory neurons.

Wickramasinghe S Rasika SR Alvania Rebecca S RS Ramanan Narendrakumar N Wood John N JN Mandai Kenji K Ginty David D DD

Neuron 20080501 4

Serum response factor (SRF) is a prototypic transcription factor that mediates stimulus-dependent gene expression. Here, we show that SRF mediates NGF signaling, axonal growth, branching, and target innervation by embryonic DRG sensory neurons. Conditional deletion of the murine SRF gene in DRGs results in no deficits in neuronal viability or differentiation but causes defects in extension and arborization of peripheral axonal projections in the target field in vivo, similar to the target innerv ...[more]

PMID: 18498735

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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

Serum response factor mediates NGF-dependent target innervation by embryonic DRG sensory neurons.

Publications

Serum response factor mediates NGF-dependent target innervation by embryonic DRG sensory neurons.

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