Deletion of Tsc2 in Nociceptors Reduces Target Innervation, Ion Channel Expression, and Sensitivity to Heat

ENeuro
Dan CarlinValeria Cavalli

Abstract

The mechanistic target of rapamycin complex 1 (mTORC1) is known to regulate cellular growth pathways, and its genetic activation is sufficient to enhance regenerative axon growth following injury to the central or peripheral nervous systems. However, excess mTORC1 activation may promote innervation defects, and mTORC1 activity mediates injury-induced hypersensitivity, reducing enthusiasm for the pathway as a therapeutic target. While mTORC1 activity is required for full expression of some pain modalities, the effects of pathway activation on nociceptor phenotypes and sensory behaviors are currently unknown. To address this, we genetically activated mTORC1 in mouse peripheral sensory neurons by conditional deletion of its negative regulator Tuberous Sclerosis Complex 2 (Tsc2). Consistent with the well-known role of mTORC1 in regulating cell size, soma size and axon diameter of C-nociceptors were increased in Tsc2-deleted mice. Glabrous skin and spinal cord innervation by C-fiber neurons were also disrupted. Transcriptional profiling of nociceptors enriched by fluorescence-associated cell sorting (FACS) revealed downregulation of multiple classes of ion channels as well as reduced expression of markers for peptidergic nociceptors...Continue Reading

Datasets Mentioned

BETA
GSE112499

Methods Mentioned

BETA
PCR
protein assay
confocal microscopy
flow cytometry
electrophoresis
Illumina Sequencing
transmission electron microscopy
RNA-seq

Key Resources (RRID) Mentioned

MGI

Software Mentioned

FastQC
FIJI
align
STAR
MetaCore
HTseq
QuantStudio
QuantStudio Real - Time PCR
DESeq2
GraphPad Prism

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