Bibliographic record
Abstract
Cerebral cortex development is a complex process that integrates both extrinsic and intrinsic mechanisms. The surrounding cellular environment triggers receptor activation, which in turn initiates components of different signalling cascades and subsequently gene transcription, influencing cell survival, proliferation, and differentiation. Genetic mutations causing a loss-of-function or gain-of-function of signalling pathways elements can lead to cortical abnormalities and result in cognitive dysfunctions. In this thesis, I examined the receptor tyrosine kinase (RTK) TrkB and TrkC, the small GTPase Ras, and the C/EBP family of transcription factors, investigating their roles during cerebral cortex development. First, I looked at the role of C/EBPs during cortical cell fate determination. I determined that inhibition of C/EBPs decrease neurogenesis, keeping precursors in an undifferentiated state and later promoting their differentiation into astrocytes, while expression of an activated form of C/EBP promoted neurogenesis and reduced astrogenesis. Moreover, the inhibition of MEK, a mediator of C/EBPβ phosphorylation, also caused a decrease in neurogenesis. Thus, activation of the MEK-C/EBP pathway biases precursor cells to become neurons rather than astrocytes, thereby acting as a differentiation switch. Second, I examined the involvement of Trk signalling during cortical development. I showed that genetic knockdown using shRNA, or inhibition using dominant negative of TrkB and TrkC lead to a decrease in proliferation and later to postnatal precursor cells depletion. Moreover, it caused a reduction in number of neurons combined with mislocalization of the generated neurons to the different cortical layers. Thus, Trk signalling plays an essential role in the regulation of cortical precursor cell proliferation and differentiation during embryonic development. Third, I elucidated the effect of Costello syndrome H-Ras mutations during cerebral cortex formation. I determined that these mutations promoted cell proliferation and astrogenesis, while reducing neurogenesis. Together, these data support a model where proper Trks/Ras/MEK/C/EBP signalling is essential for normal genesis of neurons and astrocytes and show that cortical development perturbations can ultimately lead to cognitive dysfunction as seen in Costello syndrome patients.
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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 | 0.000 | 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) | 0.000 | 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".