Pincher-generated Nogo-A signalosomes mediate growth cone collapse and retrograde transport
Bibliographic record
Abstract
The ability of adult CNS neurons to successfully regenerate their axons upon injuries such as stroke and spinal cord injury is very limited. Over the last two decades researches have focused on the challenging question of how to overcome this regenerative failure. The identification of the myelin associated neurite outgrowth inhibitor Nogo-A shed light on the inhibitory nature, compared to the PNS, of CNS myelin. Subsequent Nogo-A neutralization experiments led to successful CNS regeneration in animal models of spinal cord injury. The first part of Chapter 1 summarizes important findings regarding Nogo-A function as a neurite outgrowth inhibitor and gives insight into emerging roles of Nogo-A during development and disease. Nogo-A contains two inhibitory regions for neurite outgrowth inhibition: the Nogo66 region, also common to Nogo-B and Nogo-C, and the Nogo-A specific region, NogoΔ20. Whereas the signaling mechanisms of the Nogo66 region are well characterized, comparatively little is known about the signaling complex of NogoΔ20. Since blocking of the Nogo66 receptor complex does not completely abolish myelin inhibition of neurite outgrowth, it is of great importance to elucidate the Nogo66 receptor independent mechanism of Nogo-A signaling. Over the last few years it has become clear that endocytosis plays an active role during cellular communication. A number of surface ligand-receptor complexes are known to internalize into cells and signal from endosomes. The second part of Chapter 1 introduces endocytosis as a possible mechanism for NogoΔ20 signaling and reviews the known endocytic pathways. In Chapter 2 we find that the soluble, active NogoΔ20 fragment is internalized into neuronal cells. The internalization into early endosomes does not follow a conventional clathrin-and dynamin dependent route, it rather depends on the Pincher protein and the small GTPase Rac. This Pincher-mediated macroendocytosis of NogoΔ20 results in the formation of NogoΔ20 signalosomes that direct RhoA activation and growth cone collapse. In compartmentalized chamber cultures, NogoΔ20 is endocytosed into neurites and retrogradely transported to the cell bodies of DRG neurons, triggering RhoA activation en route and decreasing pCREB levels in cell bodies. The decrease of pCREB points towards an antagonistic regulation of the growth machinery by Nogo-A and neurotrophins. Taken together, the findings of the present thesis suggest that Pincher-dependent macroendocytosis may lead to the formation of a Nogo-A signaling endosome that is retrogradely transported from the axons to the cell body thus suppressing the neuronal growth program.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".