Expression and Manipulation of the APC-β-Catenin Pathway During Peripheral Neuron Regeneration

Abstract

Molecules and pathways that suppress growth are expressed in postmitotic neurons, a potential advantage in mature neural networks, but a liability during regeneration. In this work, we probed the APC (adenomatous polyposis coli)-β-catenin partner pathway in adult peripheral sensory neurons during regeneration. APC had robust expression in the cytoplasm and perinuclear region of adult DRG sensory neurons both before and after axotomy injury. β-catenin was expressed in neuronal nuclei, neuronal cytoplasm and also in perineuronal satellite cells. In injured dorsal root ganglia (DRG) sensory neurons and their axons, we observed paradoxical APC upregulation, despite its role as an inhibitor of growth whereas β-catenin was downregulated. Inhibition of APC in adult sensory neurons and activation of β-catenin, LEF/TCF transcriptional factors were associated with increased neuronal plasticity in vitro. Local knockdown of APC, at the site of sciatic nerve crush injury enhanced evidence for electrophysiological, behavioural and structural regeneration in vivo. This was accompanied by upregulation of β-catenin. Collectively, the APC-β-catenin-LEF/TCF transcriptional pathway impacts intrinsic mechanisms of axonal regeneration and neuronal plasticity after injury, offering new options for addressing axon regeneration.

Adipose-Derived Mesenchymal Stem Cells Applied in Fibrin Glue Stimulate Peripheral Nerve Regeneration

“…We showed that after sciatic nerve injury IB4 expression is found not only in small pain neurons but also in medium-sized neurons. IB4 is believed to be a marker of small nociceptive neurons that have unmyelinated processes in the sciatic nerve innervating the epidermis and showing lower survival both in vitro and in vivo (56). Therefore, this type of neurons is more prone to cell death as compared to medium and large diameter neurons, which is consistent with our results.…”

Major urinary protein excreted in rodent hindpaw sweat

“…Quantification of bands was through Adobe Photoshop and the band densities were normalized with those of the loading control. The approach for Western immunoblots has been previously published in work from our laboratory (Duraikannu et al, 2018).…”

“…MUPs may stimulate olfactory cells, namely vomeronasal epithelial receptors either directly or through their binding to volatile hydrocarbons. They are approximately 18-20 kDA sized protein members of the lipocalin family with eight antiparallel β-strands organized in a β barrel with additional α helices, forming a pocket that sequesters organic molecules for later release as an olfactory stimulant, mainly for avoidance by males and attraction by females (Beynon & Hurst, 2003;Gomez-Baena et al, 2014;Kwak et al, 2012;Schiefner & Skerra, 2015). We encountered unexpected patterns of MUP expression in peripheral sensory neurons of outbred laboratory mice leading, in turn, to its further unforeseen appearance, described here, in dermal hindpaw footpad sweat glands.…”

Beyond Trophic Factors: Exploiting the Intrinsic Regenerative Properties of Adult Neurons

“…In sensory neurons, knockdown of APC increased β-catenin nuclear accumulation, was associated with upregulation TCF and lymphoid enhancing binding factor (LEF) transcription factors (Figure 4). In addition, knockdown of APC in adult DRG neurons increased neurite outgrowth of both uninjured and preconditioned neurons (Duraikannu et al, 2018). Narciso et al (2009), showed that β-catenin expression increased in Galectin-3 knockout mice associated with enhanced neuronal survival and axon regeneration after traumatic nerve lesions.…”

“…Furthermore, interactions between β-catenin and TCF3 were required for SC myelination in vivo (Tawk et al, 2011). Inhibition of β-catenin and TCF activity impaired neurite outgrowth in DRG neurons in vitro (Duraikannu et al, 2018). In vivo , local knockdown of APC following nerve trunk crush injury using siRNA increased the repopulation of myelinated axons and was associated with improved indices of functional recovery.…”