DYRK1A haploinsufficiency affects the development of astroglia and oligodendroglia, and axonal conductivity in the brain
Bibliographic record
Abstract
Abstract Background: The correct development and activity of neurons and glial cells, and the interplay between them, is necessary to establish proper brain connectivity. DYRK1A encodes a protein kinase that influences neurogenesis and the morphological differentiation of neurons. Indeed, it is a gene associated with a risk of autism spectrum disorders. DYRK1A loss-of-function mutations cause a rare disorder in heterozygosity characterized by developmental delay, microcephaly, moderate-to-severe intellectual disability, speech delay or the absence of communicative language, motor dysfunctions and a distinctive facial gestalt. Ritualized behaviours and/or autism are also frequent traits in this disorder. As such, glial cell development and myelination in the brain have been explored in relation to DYRK1A haploinsufficiency syndrome.Methods: Using cell-specific markers, the developmental trajectories of cortical macroglial cells were analysed in brain sections of Dyrk1a+/- mice, a mouse model that recapitulates the main neurological features of DYRK1A syndrome. In combination with in utero electroporation, the ultrastructure of the brain white matter was studied by electron microscopy and the characteristics of the nodes of Ranvier by immunofluorescence. Myelin protein was assessed by immunoblotting and electrophysiology was performed to measure conduction velocities of evoked compound action potentials in the corpus callosum.Results: In Dyrk1a+/- mice the development of glial cells that populate the prospective neocortex was altered. An increase in astrogliogenesis produced an excess of astrocytes that persisted into adulthood, in conjunction with a delay in the production of oligodendrocyte progenitor cells and their progression along the oligodendroglial lineage. There were fewer myelinated axons in the corpus callosum of Dyrk1a+/- mice, axons that are thinner and with abnormal nodes of Ranvier. Moreover, action potential propagation along myelinated and unmyelinated callosal axons was slower in Dyrk1a+/- mutants. All these abnormalities are likely to affect neuronal circuit development and alter network synchronicity, influencing higher brain functions.Conclusions: The results obtained here indicate that disrupted macroglial development and white matter myelination contribute to the core neurological symptoms of DYRK1A syndrome, paving the way to design pharmacological interventions that ameliorate or revert these symptoms postnatally.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".