Matrix metalloproteinase activity modulates neuronal response to myelin inhibition by cleaving NgR1 and basal axonal outgrowth
Bibliographic record
Abstract
The complex wiring of the mammalian brain is established by accurate axonal guidance and synaptogenesis. These developmental processes are highly regulated by ligands and their corresponding cell surface receptors expressed on neurons. Unfortunately, the mature central nervous system (CNS) severely restricts neurite outgrowth following injury in part due to the presence of inhibitory ligands and receptors. The Nogo66 receptor (NgR1) is expressed by mature neurons and inhibits the regrowth of injured CNS neurons by binding to multiple inhibitory ligands. Further, NgR1 is highly expressed in synaptogenic areas such as the cortex and hippocampus where it regulates synaptic plasticity and restricts experience-dependent plasticity. Interestingly, NgR1 levels in neurons can be altered by proteolytic activity termed shedding, which is mediated by metalloproteinases. This process reduces cell surface full length NgR1 and generates a soluble dominant negative fragment, which has the potential to impact NgR1 function in the brain. My thesis focused on studying the impact of metalloproteinase induced shedding on NgR1 function. Herein I provide evidence that membrane anchored metalloproteinases can cleave NgR1 from neurons and attenuate responses to inhibitory cues. Membrane type metalloproteinases are expressed in the adult mouse brain and promote NgR1 shedding until late adulthood. NgR1 is shed from synaptosomes suggesting that this mechanism may regulate NgR1 function at the synapse. These results prompted us to investigate whether metalloproteinase activity can regulate axonal outgrowth through other cell surface proteins. We determined that membrane anchored metalloproteinases promote axonal outgrowth from CNS and PNS neurons. We identified several candidate targets by mass spectroscopy, which include the adhesive protein family IgLONs that are known to regulate axonal outgrowth. Together, the data presented here extends our understanding of metalloproteinase-dependent regulation of neurite outgrowth during development. In addition, our observations with NgR1 shedding by metalloproteinases suggest that this process is conserved in neurite outgrowth inhibition and restriction of synaptic plasticity.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| 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".