Skip to content

NotablePeer-reviewed

An axon-intrinsic loop restricts nerve regeneration through axonal protein synthesis

A REG3A-to-KHSRP axonal loop brakes peripheral nerve regeneration through localized mRNA translation

ByCourtney N. Buchanan, Jinyoung Lee, Samaneh Matoo, Jordan A. Headen, Marie-Claire Honoree, Molly Conway and 2 others

University of South Carolina · University of Virginia · University of New Mexico

What it is

Injured axons make the RNA-binding protein KHSRP, which promotes mRNA decay and slows nerve regeneration. A rise in axoplasmic calcium triggers KHSRP translation after axotomy, and although calcium returns to pre-injury levels within 16 hours, axonal KHSRP stays elevated because the alternating translation of two transcripts, Reg3a and Khsrp, sustains it. Secreted REG3A stimulates ER calcium release that activates PERK, raises eIF2 alpha phosphorylation, and drives further Khsrp translation. Depleting Reg3a attenuates growth-cone calcium oscillations, lowers KHSRP synthesis, reduces the axon's retractive events, and accelerates peripheral nerve regeneration.

Fig. 1 of the paper: Axon injury increases axonal REG3A mRNA and protein.
Fig. 1 from the paperAxon injury increases axonal REG3A mRNA and protein.Courtney N. Buchanan et al., Science Advances (2026), under CC BY 4.0, shown unaltered; image from PubMed Central.

Why it matters

Peripheral axons regrow slowly, and the axon-intrinsic controls that restrain their own regeneration have been poorly defined. This work identifies a self-sustaining REG3A-to-KHSRP loop, built from proteins synthesized locally in the axon, that keeps decelerating growth even after the injury calcium signal subsides within 16 hours.

Underlined numbers link to their source. Every metric and quoted figure is listed under Sources and data below.

Filed underneuroscience, nerve regeneration, axonal translation, KHSRP, peripheral nerve injury

Scored 2026-10-07How scoring works

The Frontier Score, in full

How this entry's score is built, term by term. Open any pillar to see each sub-metric's raw value, how it maps to 0 to 100, and a link to its source (OpenAlex for most sub-metrics that combine several sources, NIH iCite where its ratio is part of field-normalized impact).
Evidence 89Impact 0Novelty 66
The three pillars as one shape: a result strong on every axis fills the triangle.
How the Frontier Score is calculated for this breakthrough
TermScoreWeightPoints
EvidenceHow established and verifiable the result is.89× 0.2522.2
ImpactHow much the result matters, judged field-relative and by current momentum.0× 0.250.1
NoveltyHow genuinely new the result is, and how fast-moving.66× 0.5032.8
Weighted pillars55.1
Frontier recency1 month since publication× 0.94
IntegrityNot retracted× 1
Frontier Score52
Confidence: Early signal. Early signal: little citation history yet, so impact is an estimate and may shift as the work is taken up.Early signal: little citation history yet, so impact is an estimate and may shift as the work is taken up.

Every sub-metric, traced to its source

Evidence89
Evidence sub-metrics
Sub-metricRaw value0 to 100WeightPointsSource
Peer review & venueWhether the work has cleared peer review, and how selective its venue is. Peer review is necessary but not sufficient: before citations accrue, a fresh result in one of the five general flagships (Nature, Science, Cell, NEJM, the Lancet) is a stronger evidence signal than one in a selective specialist or society journal, which in turn outranks one in a legitimate but very high-volume mega-journal, and any of them outranks a preprint that has not been reviewed at all.Maps to 0 to 100: Peer-reviewed article graded by venue tier: flagship journal (Nature, Science, Cell, NEJM, the Lancet) 100; selective journal (every other journal the index admits: the specialist journals of those families, JAMA, PNAS, Physical Review Letters and X) 90; high-volume mega-journal (Nature Communications, Science Advances) 78; venue not recorded 88. Other records: review 90, book 70, dataset 60, preprint 45, an article that has not been peer reviewed 45, other 55.Peer-reviewed, high-volume journal780.3023.4OpenAlex type / primary_location / source
CorroborationIndependent corroboration that the result is on the record and reaching beyond a single source, read as the BREADTH of independent records rather than the size of the citation pile. Counts how many of the five independent citation indices (OpenAlex, Crossref, Semantic Scholar, OpenCitations, Europe PMC) report a citation count for the work at all, zero included, plus orthogonal, non-citation lines of corroboration: citation in Wikipedia, registered clinical trials or clinical citations, released datasets or software or a repository copy, public funding on record, and technical-community discussion. Citation MAGNITUDE is deliberately judged under Impact, not here, so Evidence and Impact measure genuinely different things instead of both rewarding the same citation pile twice.Maps to 0 to 100: Starts at 28 and rises by 9 for each of the five independent citation indices that returns a citation count for the work (zero counts; OpenCitations returns zero even for a DOI it does not hold) and by 6 for each orthogonal non-citation line (Wikipedia, clinical trials or clinical citations, open datasets, software or a repository copy, public funding, community discussion), up to the top of the 0-100 scale.5 of 5 citation indices report a count, 2 independent non-citation lines850.3025.5OpenAlex, Crossref, Semantic Scholar, OpenCitations, Europe PMC, DataCite, NIH RePORTER, Wikipedia, Hacker News count of indices that report a count for the work + orthogonal reach
VerifiabilityHow openly the result can be read, reused, and reproduced. Rewards open access, a Creative Commons BY or CC0 license, a green repository copy anyone can archive, openly minable full text, and released datasets or software a reader can actually run. Cross-checked across OpenAlex, Unpaywall, Europe PMC, and DataCite.Maps to 0 to 100: Closed access 45; open access 88; any Creative Commons BY license (including the NC, ND and SA variants) or CC0 100. A repository copy raises the floor to 85, openly minable full text to 90, and released data or software to 92.Open access (gold), CC-BY, repository copy1000.2020.0OpenAlex, Unpaywall, Europe PMC, DataCite is_oa / license / has_repository_copy / open datasets
IntegrityRetraction and post-publication correction status. A retracted result is not evidence of anything and collapses the whole Frontier Score; a correction or expression of concern is a softer flag. Read across OpenAlex and Crossref (both update-to and updated-by notices).Maps to 0 to 100: Clean 100; a correction or expression of concern 75; retracted 0. Flagged if OpenAlex OR Crossref records the notice.No retraction or concern on record1000.2020.0OpenAlex, Crossref is_retracted / update-to / updated-by
Impact0
Impact sub-metrics
Sub-metricRaw value0 to 100WeightPointsSource
Field-normalized impactImpact relative to the world average for the same field, year, and type, so a small field and a large field are judged fairly. Triangulates three independent field-normalized measures: OpenAlex's Field-Weighted Citation Impact, its citation percentile within the exact field-and-year cohort, and the NIH iCite Relative Citation Ratio. 1.0x is average; the percentile is the share of same-field, same-year work it out-cites.Maps to 0 to 100: Each ratio (1.0 = field average) maps 1.0 to 50, 3.0 to 75, 9.0 to 90; the field+year percentile maps directly (top 1% -> ~99). The available measures are averaged. When none is available yet (very recent work), this sub-metric is left out and Impact is computed from the others.top 99% of field-year vs field10.450.4OpenAlex, NIH iCite fwci / citation_normalized_percentile / relative_citation_ratio
Influential citationsCitations that genuinely build on the work rather than mention it in passing (Semantic Scholar's influential-citation measure). A sharper signal of real impact than a raw count.Maps to 0 to 100: Saturating: 15 influential citations maps to 50, and none maps to 0. When Semantic Scholar has no measure for the work, this sub-metric is left out and Impact is computed from the others.0 influential00.200.0Semantic Scholar influentialCitationCount
Citation velocityCitations received in the trailing twelve months (estimated from yearly citation counts: this year's so far plus the share of last year's that falls inside the window), judged as a rate rather than a lifetime total. Momentum is what a frontier index cares about: a result being taken up fast right now is landing, whether its lifetime pile is large or still small. Where an expected field citation rate is known, the momentum is also read relative to it, so a fast-moving result in a quiet field is not overlooked.Maps to 0 to 100: Saturating: 30 citations in the last twelve months maps to 50. When NIH iCite provides the field's expected rate, this is blended evenly with the ratio of observed to expected momentum.0 in last 12 months00.350.0OpenAlex, NIH iCite counts_by_year / field_citation_rate
Novelty66
Novelty sub-metrics
Sub-metricRaw value0 to 100WeightPointsSource
Conceptual noveltyHow genuinely new the contribution is, measured at publication from the work's OWN content, not its date: how atypical its combination of research areas is versus all prior work, and whether it builds on a broad, deep base rather than only the newest papers in a fast-moving area. This is what separates a real advance from a recent-but-commodity result, and it needs no forward citations, so it is stable for brand-new work. An honestly noisy proxy (even state-of-the-art novelty measures agree only moderately with expert judgment), so it carries bounded weight and never drives the ranking alone.Maps to 0 to 100: Two publication-time signals, each 0-100. The primary one is atypical combination: how unusual the work's median pairing of research topics is versus the prior literature, by pointwise mutual information (a pairing made far more often than chance scores low). The second, foundational reach (the median age of the work's references and the share older than five years), can only lift it: when reach is higher, the score rises by 35% of the gap, and it is never lowered. When only one signal is measurable it is used alone; when neither is (a work too thin in topics or references), this sub-metric is left out and Novelty is computed from the other three. A review is damped to 60%.Median topic pairing Nerve injury and regeneration x Pain Mechanisms and Treatments (9,885 prior works made this pairing); builds on refs a median 12.8y deep460.4520.8OpenAlex topics + referenced_works (publication-time)
RecencyHow recently the work appeared. The frontier is now, so newer scores higher.Maps to 0 to 100: Exponential decay with a 12-month half-life from the publication date.This month920.3027.7OpenAlex publication_date
Attention accelerationWhether attention is rising: citations in the latest full year versus the year before. Accelerating interest signals an active, opening frontier.Maps to 0 to 100: Latest/prior-year ratio: 1x maps to 50, 2x to 75, 4x to 100. The prior year counts as at least 3 citations, so a jump from one citation to a few is not read as explosive growth. With no citations in the latest full year it reads as unknown, and unknown is neutral (50).Not enough history500.105.0OpenAlex counts_by_year
Edge of reviewPreprints sit ahead of the peer-review process and brand-new papers have only just cleared it. Both earn novelty here (while a preprint is discounted under Evidence), because that is where the frontier forms first.Maps to 0 to 100: Preprint 95; any other record 80 when under 6 months old, 65 under 18 months, 45 after that.Peer-reviewed record800.1512.0OpenAlex type / publication_date
ProvenanceAll sources

Sources and data

The source figures behind this entry, grouped by the source that holds them: up to five citation indices cross-checked, field-normalized impact, then real-world reach (Wikipedia, community discussion, clinical trials, released data and public funding) where it exists. Each value links to its record.

OpenAlex

Primary record
Field-weighted citation impact
0.0x field average
Citation percentile
Top 99% of its field-year
Publication date
2026-08-26

Crossref

Citations
0
Works it builds on
52
Funders on record
4

Semantic Scholar

Citations, all versions
0
Influential citations
0

OpenCitations

Citations
0

Europe PMC

Citations
0

NIH iCite

Potential to translate
5%

Unpaywall

Reuse license
CC-BY

NIH RePORTER

NIH grants funding it
2
NIH award funding
$4,393,765

Figures quoted in the write-up

FigureValueSource
time for axoplasmic calcium to return to pre-injury levels after axotomy16 hoursScience Advances
transcripts whose alternating translation sustains axonal KHSRP (Reg3a and Khsrp)twoScience Advances
For the authors

Show this score where your work lives

A badge for your lab page, your CV or the paper's code repository. It links readers to this entry, and it always carries the entry's current score.
This paper's Frontier Score badge, as it appears where you place itLive preview
<a href="https://frontierresearch.co/breakthroughs/an-axon-intrinsic-loop-restricts-nerve-regeneration-thro-w4415675826?utm_source=badge&amp;utm_medium=badge&amp;utm_campaign=author-kit"><img src="https://frontierresearch.co/api/badge/W4415675826.svg" alt="Frontier Score for this paper" height="20"></a>

For a lab or personal website, a CV page, or anywhere that takes HTML.

The number is live. The badge is drawn from the same signals as this page, so it never shows a score the entry does not. Every entry is re-checked weekly against the same public sources, and a result's standing eases as it ages, so the active edge of the field stays on top. How scoring works

Something wrong or out of date? Write to hello@frontierresearch.co and the entry will be corrected.

NeuroscienceThe whole field

Back to the Frontier Index, or browse every breakthrough by date.

The Frontier Brief

The week's Neuroscience, scored.

Every Monday, up to six of the week's new Neuroscience entries in the index, each with its score and a one-line read on why it matters, then the week's best from the rest of the frontier. What you get

Prefer a feed reader? Follow Neuroscience by RSS

One email a week: up to six of the week's new Neuroscience entries, scored, then the best elsewhere. Unsubscribe anytime.