The cover paper of PNAS (1) presents a concept for promoting the neuronal regenerative potential by engineering the expression of a stem cell marker, Prom1. Axon regeneration is regulated by a neuron-intrinsic transcriptional program that is suppressed during development but that can be reactivated following peripheral nerve injury. The authors identified Prom1, which encodes the stem cell marker prominin-1, as a regulator of the axon regeneration program. They provide evidence that a reduction in cholesterol synthesis empowers neuronal regrowth capacity. This work suggests that Food and Drug Administration-approved cholesterol-lowering drugs are potential candidates for neuroregenerative medicine.
Data show that elevation of cellular cholesterol levels with water-soluble cholesterol (cholesterol/MβCD complex) significantly reduced axonal regrowth while the neurons treated with MβCD display extensively arborized neurites with a dramatic increase in axon growth length, although it is distinguished from the characteristic axon elongation in the regenerative phase, possibly due to the overall depletion of cholesterol from different cellular domains.
Collectively, the data suggest that prominin-1 plays a role in modulating cellular architecture by regulating the expression of cholesterol metabolism-related genes, shifting the physiological condition from a naïve state to a regenerative state, which leads to enhanced axon regeneration after injury.
Image credit: Yongcheol Cho.
(1) Jinyoung Lee, Jung Eun Shin, Bohm Lee, Hyemin Kim, Yewon Jeon, Seung Hyun Ahn, Sung Wook Chi, and Yongcheol Cho (2020) The stem cell marker Prom1 promotes axon regeneration by down-regulating cholesterol synthesis via Smad signaling.
PNAS 117 (27) 15955-15966; first published June 17, 2020 https://doi.org/10.1073/pnas.1920829117