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

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. Copyright © 2020 the Author(s). Published by PNAS.

Citation

Jinyoung Lee, Jung Eun Shin, Bohm Lee, Hyemin Kim, Yewon Jeon, Seung Hyun Ahn, Sung Wook Chi, Yongcheol Cho. 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 Jul 07;117(27):15955-15966

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PMID: 32554499

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