Protein Kinase A Regulates the Sensitivity of Spinal Commissural Axon Turning to Netrin-1 But Does Not Switch between Chemoattraction and Chemorepulsion
Bibliographic record
Abstract
Bifunctional axon guidance cues have been grouped into two classes depending on whether changes in intracellular cAMP or cGMP switch the response of the growth cone between attraction and repulsion. According to this model, axons respond to netrin-1, a group I guidance cue, as a chemoattractant when cAMP levels are high in the growth cone but switch and are repelled when the intraneuronal concentration of cAMP is low. The model is complicated by the proposal that cAMP-dependent kinase, protein kinase A (PKA), functions as a downstream effector for several guidance cues, including netrin-1, suggesting a close inter-relationship between guidance cue signal transduction and mechanisms regulating the switch between attraction and repulsion. Here, we examine possible interactions between netrin-1-mediated axon guidance and cAMP signaling in embryonic rat spinal commissural neurons. We report that netrin-1 does not alter the concentration of cAMP or PKA activity in these neurons across a wide range of netrin-1 concentrations and time points after application, leading us to conclude that netrin-1 does not regulate PKA in these cells. In contrast to the cyclic nucleotide switch model, we report that, despite inhibiting PKA, embryonic spinal commissural axons were always attracted to netrin-1 and never repelled. Instead, manipulating PKA regulated the sensitivity of chemoattraction to netrin-1: PKA inhibition reduced, and PKA activation increased, the distance over which axons turn toward a source of netrin-1. These findings indicate that the mechanisms underlying cyclic nucleotide-regulated switching are separable from the signal transduction mechanisms required for chemoattraction to netrin-1.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".