Detection of PERK Signaling in the Central Nervous System

Lei, Zhixin; Stone, Sarrabeth; Lin, Wensheng

doi:10.1007/978-1-0716-1732-8_15

Cited by 1 publication

(1 citation statement)

References 25 publications

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“…At d1 post-fracture, Zfp263 , Nfkb2 and Stat1 were significantly upregulated, TFs associated with the regulation of inflammation in other systems ( Nfkb2 and Stat1 21–23 ). At d14 post-fracture, several TFs were identified, including regulators of neural development ( Maz and Gata2) 24,25 , NGF target genes ( Egr3 ) 26,27 , negative regulators of neuronal apoptosis ( Klf2 ) 28 , as well as stress-responsive genes ( Atf4 ) 29 . Interestingly, common neuronal markers of nerve injury (e.g.…”

Section: Resultsmentioning

confidence: 99%

Mapping Somatosensory Afferent Circuitry to Bone Identifies Neurotrophic Signals Required for Fracture Healing

Xu,

Thottappillil,

Cherief

et al. 2024

Preprint

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SummaryThe profound pain accompanying bone fracture is mediated by somatosensory neurons, which also appear to be required to initiate bone regeneration following fracture. Surprisingly, the precise neuroanatomical circuitry mediating skeletal nociception and regeneration remains incompletely understood. Here, we characterized somatosensory dorsal root ganglia (DRG) afferent neurons innervating murine long bones before and after experimental long bone fracture in mice. Retrograde labeling of DRG neurons by an adeno-associated virus with peripheral nerve tropism showed AAV-tdT signal. Single cell transcriptomic profiling of 6,648 DRG neurons showed highest labeling across CGRP+ neuron clusters (6.9-17.2%) belonging to unmyelinated C fibers, thinly myelinated Aδ fibers and Aβ-Field LTMR (9.2%). Gene expression profiles of retrograde labeled DRG neurons over multiple timepoints following experimental stress fracture revealed dynamic changes in gene expression corresponding to the acute inflammatory (S100a8,S100a9) and mechanical force (Piezo2). Reparative phase after fracture included morphogens such asTgfb1, Fgf9andFgf18. Two methods to surgically or genetically denervate fractured bones were used in combination with scRNA-seq to implicate defective mesenchymal cell proliferation and osteodifferentiation as underlying the poor bone repair capacity in the presence of attenuated innervation. Finally, multi-tissue scRNA-seq and interactome analyses implicated neuron-derived FGF9 as a potent regulator of fracture repair, a finding compatible with in vitro assessments of neuron-to-skeletal mesenchyme interactions.

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