Neuronal cytoskeletal gene dysregulation and mechanical hypersensitivity in a rat model of Rett syndrome

Abstract

Children with Rett syndrome show abnormal cutaneous sensitivity. The precise nature of sensory abnormalities and underlying molecular mechanisms remain largely unknown. Rats with methyl-CpG binding protein 2 (MeCP2) mutation, characteristic of Rett syndrome, show hypersensitivity to pressure and cold, but hyposensitivity to heat. They also show cutaneous hyperinnervation by nonpeptidergic sensory axons, which include subpopulations encoding noxious mechanical and cold stimuli, whereas peptidergic thermosensory innervation is reduced. MeCP2 knockdown confined to dorsal root ganglion sensory neurons replicated this phenotype in vivo, and cultured MeCP2-deficient ganglion neurons showed augmented axonogenesis. Transcriptome analysis revealed dysregulation of genes associated with cytoskeletal dynamics, particularly those controlling actin polymerization and focal-adhesion formation necessary for axon growth and mechanosensory transduction. Down-regulation of these genes by topoisomerase inhibition prevented abnormal axon sprouting. We identified eight key affected genes controlling actin signaling and adhesion formation, including members of the Arhgap, Tiam, and cadherin families. Simultaneous virally mediated knockdown of these genes in Rett rats prevented sensory hyperinnervation and reversed mechanical hypersensitivity, indicating a causal role in abnormal outgrowth and sensitivity. Thus, MeCP2 regulates ganglion neuronal genes controlling cytoskeletal dynamics, which in turn determines axon outgrowth and mechanosensory function and may contribute to altered pain sensitivity in Rett syndrome.

A clinical case–control comparison of epidermal innervation density in Rett syndrome

“…Overall, with the important caveat that our patient sample was small and one of the clinical convenience, our preliminary observations are in line with recent work on animal models demonstrating peripheral tactile abnormalities in Mecp2‐deficient mice (Orefice et al, ) and rats (Bhattacherjee et al, ). One notable difference in our clinical observations, however, was the cutaneous hyperinnervation appeared to be primarily a result of proliferation of peptidergic fibers.…”

“…Recent findings have also documented pronounced changes in sensory olfactory and trigeminal neurons (Degano, Park, Penati, Li, & Ronnett, 2014) providing further evidence of the importance of MeCP2's role in activity-dependent maturation of sensory circuitry. Although speculative, it may be that the complex morphological ENF observations reflect dorsal root ganglion (DRG) neuron abnormalities, as suggested also by Bhattacherjee et al (2017) in their documented pattern of somatosensory deficits associated with MECP2 mutation, that appear to be cell-autonomous to primary sensory neurons of the DRG. More generally, MeCP2 may play a role in the maturation of peripheral somatosensory circuitry as well.…”

“…result of proliferation of peptidergic fibers. In their preclinical model,Bhattacherjee et al (2017) also discovered cutaneous hyperinnervation of intra-ENFs, but the proliferation consisted predominantly of nonpeptidergic sensory axons. The functional significance of the similarities (hyperinnervation) and differences (peptidergic vs. nonpeptidergic sensory axons) between our clinical observations and preclinical models remains to be determined.…”

Quantitative proteomic analysis of Rett iPSC-derived neuronal progenitors

“…The most significant upregulated proteins are associated with GO terms 'cell-cell adhesion' and 'actin cytoskeleton organization'. In previous studies, dysregulation of the actin cytoskeletal organization was observed on transcriptional level, and associated with phenotypic alterations as abnormal dendrite formation and dendritic growth (39)(40)(41)(42). However, these studies reported a transcriptional down regulation of the mentioned pathways, which is in contrast to our results.…”

Outside-in: Rethinking the etiology of autism spectrum disorders

“…Together with a growing body of other research (3,4,(16)(17)(18), our work highlights that peripheral sensory neurons have a major role in ASD and that selective treatment of these neurons has the potential to improve some developmental and behavioral abnormalities associated with ASD. We are moving toward measuring touch overreactivity in humans with ASD and pursuing modulation of peripheral neuron excitability as a potential clinical therapy.…”