The transcription factor c-Jun drives the reprogramming of myelin and Remak Schwann cells into repair Schwann cells that support axon regrowth after peripheral nerve injury. Wagstaff et al. (eLife 2021;10:e62232) showed that this repair program fails in two clinically important settings, aging and chronic denervation, because Schwann cell c-Jun levels fall, and that genetically restoring c-Jun rescues regeneration in mice. Their discussion defines four unresolved questions that jointly ask how completely, and through what mechanisms and upstream signals, c-Jun controls nerve repair: (1) whether Schwann cell c-Jun determines repair outcomes beyond initial axon regrowth, namely the duration of sustained axon growth, sprouting, axonal misrouting, target reinnervation, and synapse reformation; (2) whether the proposed autocrine Sonic hedgehog (Shh) loop regulates c-Jun in vivo; (3) the mechanisms by which c-Jun levels influence nerve atrophy during chronic denervation, including roles in Schwann cell death and proliferation; and (4) how c-Jun integrates with other repair-phenotype regulators (STAT3, merlin, H3K27-trimethylation-related epigenetic controls) into a molecular framework for therapeutic intervention.

Background

After a peripheral nerve is cut or crushed, the segment distal to the injury undergoes Wallerian degeneration, the breakdown of severed axons and their myelin sheaths. The myelinating and non-myelinating (Remak) Schwann cells of the distal stump do not merely die back: within days they reprogram into repair Schwann cells, a transient phenotype specialized for regeneration that clears myelin debris, secretes neurotrophic factors, and elongates and branches to form regeneration tracks (the bands of Büngner) that guide regrowing axons back to their targets. The transcription factor c-Jun, a component of the AP-1 transcription factor family, is a master regulator of this reprogramming: Schwann-cell-specific deletion of c-Jun produces dysfunctional repair cells and severely impaired functional recovery (Arthur-Farraj et al. 2012), while graded c-Jun overexpression affects development, remyelination, and tumorigenesis in a gene-dosage-dependent manner (Fazal et al. 2017).

Regeneration nevertheless fails in two common settings. In aged animals and humans, repair-cell activation falters. And because axons regenerate slowly (roughly 1 mm per day in humans), the distal stump of a nerve requiring a long regrowth distance remains denervated for months; during this chronic denervation the repair phenotype fades, Schwann cells are gradually lost, and the nerve shrinks, so that late-arriving axons find an atrophic, unsupportive stump. Wagstaff, Gomez-Sanchez and colleagues (eLife 2021) tied both failures to one mechanism: c-Jun protein falls in repair Schwann cells of aged mice and of chronically denervated nerves, and genetically restoring c-Jun levels in Schwann cells returns regeneration to control levels in both settings. Their data also implicated Sonic hedgehog (Shh), a secreted morphogen signal acting through the Smoothened receptor, as an upstream signal: injured nerves of Schwann-cell-specific Shh knockout (Shh cKO) mice show reduced c-Jun activation, and Shh agonists elevate c-Jun in cultured Schwann cells, consistent with an injury-induced autocrine Shh loop that helps sustain c-Jun and the repair phenotype. The source's Discussion presents the in vivo action of this loop as unresolved and proposes testing it by combining Schwann-cell-specific Shh conditional knockout mice with Shh agonists and antagonists, with regeneration outcomes as readouts. Other dedicated regulators of the repair phenotype are known: STAT3 (a transcription factor activated by cytokine and growth-factor signaling), required for the long-term survival of repair cells during nerve regeneration (Benito et al. 2017); the tumor suppressor merlin (encoded by NF2); and epigenetic controls related to histone H3 lysine 27 trimethylation (H3K27me3, a repressive chromatin mark whose release permits activation of repair-state genes). Later work added another layer: during aging and chronic denervation, repair Schwann cells can transition into a senescent state, ceasing division and secreting inflammatory, axon-growth-inhibitory factors collectively called the senescence-associated secretory phenotype (Fuentes-Flores et al. 2023).

The eLife paper closes by defining what remains unknown, and these questions constitute the present problem. Together they ask how completely c-Jun, the central node of the repair program, controls the outcome of nerve repair — which repair processes it governs, what upstream signals (notably Shh) set its levels in vivo, how it acts on the progressive atrophy of chronically denervated nerves, and how it combines with the other repair-cell regulators into a molecular framework that can be targeted therapeutically in peripheral nerve repair.

Problem Statement

As posed by the Discussion of Wagstaff et al. (eLife 2021;10:e62232), determine the full causal role of Schwann cell c-Jun in peripheral nerve repair and its integration into the molecular framework of repair Schwann cell regulation. The common objective is to establish how completely c-Jun governs repair outcomes after nerve injury — including in the settings where regeneration fails, aging and chronic denervation — what upstream signals set its levels, how it acts on the chronically denervated nerve, and how it combines with other repair-phenotype regulators. Concretely:

(1) Functional scope: to what extent does c-Jun in Schwann cells determine the other critical aspects of nerve repair beyond initial axon regrowth — the length of time neurons are able to sustain axon growth after injury, axon sprouting, axonal misrouting, target reinnervation, and synapse reformation? These endpoints concern whether regenerating axons reach and reconnect with their targets, beyond the number of axons present in the distal stump.

(2) Upstream Shh control: does the proposed autocrine Sonic hedgehog signaling loop regulate Schwann cell c-Jun levels and the repair phenotype in vivo?

(3) Nerve atrophy mechanisms: by what mechanisms do c-Jun levels influence the atrophy of chronically denervated nerves — in particular, what are c-Jun's roles in Schwann cell death and proliferation during chronic denervation, and how do these relate to the loss of Schwann cells, nerve shrinkage, and the decline of repair support over denervation time?

(4) Integration with other regulators: how does the impairment of c-Jun combine with the other known regulators of the repair Schwann cell phenotype — STAT3, merlin, and H3K27-trimethylation-related epigenetic controls? The source identifies extending the study of c-Jun to these other regulators as a basis for developing molecular interventions for promoting repair in the PNS.

These four strands are the open points raised in the source's Discussion and are the four components of one common objective.

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