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  • The stem cell marker Prom1 promotes axon regeneration by down-regulating cholesterol synthesis via Smad signaling.

The stem cell marker Prom1 promotes axon regeneration by down-regulating cholesterol synthesis via Smad signaling.

Proceedings of the National Academy of Sciences of the United States of America (2020-06-20)
Jinyoung Lee, Jung Eun Shin, Bohm Lee, Hyemin Kim, Yewon Jeon, Seung Hyun Ahn, Sung Wook Chi, Yongcheol Cho
ABSTRACT

Axon regeneration is regulated by a neuron-intrinsic transcriptional program that is suppressed during development but that can be reactivated following peripheral nerve injury. Here we identify Prom1, which encodes the stem cell marker prominin-1, as a regulator of the axon regeneration program. Prom1 expression is developmentally down-regulated, and the genetic deletion of Prom1 in mice inhibits axon regeneration in dorsal root ganglion (DRG) cultures and in the sciatic nerve, revealing the neuronal role of Prom1 in injury-induced regeneration. Elevating prominin-1 levels in cultured DRG neurons or in mice via adeno-associated virus-mediated gene delivery enhances axon regeneration in vitro and in vivo, allowing outgrowth on an inhibitory substrate. Prom1 overexpression induces the consistent down-regulation of cholesterol metabolism-associated genes and a reduction in cellular cholesterol levels in a Smad pathway-dependent manner, which promotes axonal regrowth. We find that prominin-1 interacts with the type I TGF-β receptor ALK4, and that they synergistically induce phosphorylation of Smad2. These results suggest that Prom1 and cholesterol metabolism pathways are possible therapeutic targets for the promotion of neural recovery after injury.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Methyl-β-cyclodextrin, powder, BioReagent, suitable for cell culture
Sigma-Aldrich
Poly-D-lysine hydrobromide, mol wt 70,000-150,000
Sigma-Aldrich
Cholesterol-Water Soluble, powder, BioReagent, suitable for cell culture
Sigma-Aldrich
Deoxyribonuclease I from bovine pancreas, lyophilized powder, Protein ≥85 %, ≥400 Kunitz units/mg protein
Sigma-Aldrich
Chicken Extracellular Chondroitin Sulfate Proteoglycans