The stem cell marker <i>Prom1</i> promotes axon regeneration by down-regulating cholesterol synthesis via Smad signaling

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 <i>Prom1</i>, which encodes the stem cell marker prominin-1, as a regulator of the axon regeneration program. <i>Prom1</i> expression is developmentally down-regulated, and the genetic deletion of <i>Prom1</i> in mice inhibits axon regeneration in dorsal root ganglion (DRG) cultures and in the sciatic nerve, revealing the neuronal role of <i>Prom1</i> 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. <i>Prom1</i> 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 <i>Prom1</i> and cholesterol metabolism pathways are possible therapeutic targets for the promotion of neural recovery after injury.