Clustered Protocadherins Are Required for Building Functional Neural Circuits
Bibliographic record
Abstract
Neuronal identity is generated by the cell-surface expression of clustered protocadherin (Pcdh) isoforms. In mice, 58 isoforms from three gene clusters, Pcdhα, Pcdhβ, and Pcdhγ, are differentially expressed in neurons. Since cis-heteromeric Pcdh oligomers on the cell surface interact homophilically with that in other neurons in trans, it has been thought that the Pcdh isoform repertoire determines the binding specificity of synapses. We previously described the cooperative functions of isoforms from all three Pcdh gene clusters in neuronal survival and synapse formation in the spinal cord. However, the neuronal loss and the following neonatal lethality prevented an analysis of the postnatal development and characteristics of the clustered-Pcdh-null (Δαβγ) neural circuits. Here, we used two methods, one to generate the chimeric mice that have transplanted Δαβγ neurons into mouse embryos, and the other to generate double mutant mice harboring null alleles of both the Pcdh gene and the proapoptotic gene Bax to prevent neuronal loss. First, our results showed that the surviving chimeric mice that had a high contribution of Δαβγ cells exhibited paralysis and died in the postnatal period. An analysis of neuronal survival in postnatally developing brain regions of chimeric mice clarified that many Δαβγ neurons in the forebrain were spared from apoptosis, unlike those in the reticular formation of the brainstem. Second, in Δαβγ/Bax null double mutants, the central pattern generator for locomotion failed to create a left-right alternating pattern even in the absence of neurodegeneraton. Third, calcium imaging of cultured hippocampal neurons showed that the network activity of Δαβγ neurons tended to be more synchronized and lost the variability in the number of simultaneously active neurons observed in the control network. Lastly, a comparative analysis for trans-homophilic interactions of the exogenously introduced single Pcdh-γA3 isoforms between the control and the Δαβγ neurons suggested that the isoform-specific trans-homophilic interactions require a complete match of the expressed isoform repertoire at the contacting sites between interactive neurons. These results suggested that combinations of clustered Pcdh isoforms are required for building appropriate neural circuits.
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 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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 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".