LRRTMs and Neuroligins Bind Neurexins with a Differential Code to Cooperate in Glutamate Synapse Development
Bibliographic record
Abstract
Leucine-rich repeat transmembrane neuronal proteins (LRRTMs) were recently found to instruct presynaptic and mediate postsynaptic glutamatergic differentiation. In a candidate screen, here we identify neurexin-1beta lacking an insert at splice site 4 (-S4) as a ligand for LRRTM2. Neurexins bind LRRTM2 with a similar affinity but distinct code from the code for binding neuroligin-1 (the predominant form of neuroligin-1 at glutamate synapses, containing the B splice site insert). Whereas neuroligin-1 binds to neurexins 1, 2, and 3 beta but not alpha variants, regardless of insert at splice site 4, LRRTM2 binds to neurexins 1, 2, and 3 alpha and beta variants specifically lacking an insert at splice site 4. We further show that this binding code is conserved in LRRTM1, the family member linked to schizophrenia and handedness, and that the code is functional in a coculture hemisynapse formation assay. Mutagenesis of LRRTM2 to prevent binding to neurexins abolishes presynaptic inducing activity of LRRTM2. Remarkably, mutagenesis of neurexins shows that the binding face on neurexin-1beta (-S4) is highly overlapping for the structurally distinct LRRTM2 and neuroligin-1 partners. Finally, we explore here the interplay of neuroligin-1 and LRRTM2 in synapse regulation. In neuron cultures, LRRTM2 is more potent than neuroligin-1 in promoting synaptic differentiation, and, most importantly, these two families of neurexin-binding partners cooperate in an additive or synergistic manner. Thus, we propose a synaptic code hypothesis suggesting that neurexins are master regulators of the cooperative activities of LRRTMs and neuroligins.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 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".