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Etv1 inactivation reveals proprioceptor subclasses that reflect the level of NT3 expression in muscle targets.

ABSTRACT: The organization of spinal reflex circuits relies on the specification of distinct classes of proprioceptive sensory neurons (pSN), but the factors that drive such diversity remain unclear. We report here that pSNs supplying distinct skeletal muscles differ in their dependence on the ETS transcription factor Etv1 for their survival and differentiation. The status of Etv1-dependence is linked to the location of proprioceptor muscle targets: pSNs innervating hypaxial and axial muscles depend critically on Etv1 for survival, whereas those innervating certain limb muscles are resistant to Etv1 inactivation. The level of NT3 expression in individual muscles correlates with Etv1-dependence and the loss of pSNs triggered by Etv1 inactivation can be prevented by elevating the level of muscle-derived NT3-revealing a TrkC-activated Etv1-bypass pathway. Our findings support a model in which the specification of aspects of pSN subtype character is controlled by variation in the level of muscle NT3 expression and signaling.

SUBMITTER: de Nooij JC

PROVIDER: S-EPMC3763960 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Etv1 inactivation reveals proprioceptor subclasses that reflect the level of NT3 expression in muscle targets.

de Nooij Joriene C JC Doobar Staceyann S Jessell Thomas M TM

Neuron 20130301 6

The organization of spinal reflex circuits relies on the specification of distinct classes of proprioceptive sensory neurons (pSN), but the factors that drive such diversity remain unclear. We report here that pSNs supplying distinct skeletal muscles differ in their dependence on the ETS transcription factor Etv1 for their survival and differentiation. The status of Etv1-dependence is linked to the location of proprioceptor muscle targets: pSNs innervating hypaxial and axial muscles depend criti ...[more]

PMID: 23522042

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Project description:I(h), which influences neuronal excitability, has recently been measured in vivo in sensory neuron subtypes in dorsal root ganglia (DRGs). However, expression levels of HCN (hyperpolarization-activated cyclic nucleotide-gated) channel proteins that underlie I(h) were unknown. We therefore examined immunostaining of the most abundant isoforms in DRGs, HCN1 and HCN2 in these neuron subtypes. This immunostaining was cytoplasmic and membrane-associated (ring). Ring-staining for both isoforms was in neurofilament-rich A-fiber neurons, but not in small neurofilament-poor C-fiber neurons, although some C-neurons showed cytoplasmic HCN2 staining. We recorded intracellularly from DRG neurons in vivo, determined their sensory properties (nociceptive or low-threshold-mechanoreceptive, LTM) and conduction velocities (CVs). We then injected fluorescent dye enabling subsequent immunostaining. For each dye-injected neuron, ring- and cytoplasmic-immunointensities were determined relative to maximum ring-immunointensity. Both HCN1- and HCN2-ring-immunointensities were positively correlated with CV in both nociceptors and LTMs; they were high in A?-nociceptors and A?/?-LTMs. High HCN1 and HCN2 levels in A?/?-neurons may, via I(h), influence normal non-painful (e.g. touch and proprioceptive) sensations as well as nociception and pain. HCN2-, not HCN1-, ring-intensities were higher in muscle spindle afferents (MSAs) than in all other neurons. The previously reported very high I(h) in MSAs may relate to their very high HCN2. In normal C-nociceptors, low HCN1 and HCN2 were consistent with their low/undetectable I(h.) In some C-LTMs HCN2-intensities were higher than in C-nociceptors. Together, HCN1 and HCN2 expressions reflect previously reported I(h) magnitudes and properties in neuronal subgroups, suggesting these isoforms underlie I(h) in DRG neurons. Expression of both isoforms was NT3-dependent in cultured DRG neurons. HCN2-immunostaining in small neurons increased 1 day after cutaneous inflammation (CFA-induced) and recovered by 4 days. This could contribute to acute inflammatory pain. HCN2-immunostaining in large neurons decreased 4 days after CFA, when NT3 was decreased in the DRG. Thus HCN2-expression control differs between large and small neurons.

Dataset Information

Etv1 inactivation reveals proprioceptor subclasses that reflect the level of NT3 expression in muscle targets.

Publications

Etv1 inactivation reveals proprioceptor subclasses that reflect the level of NT3 expression in muscle targets.

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