The Role of Pocket Proteins pRb and p107 in Radial Migration and Axon Guidance through Cell Cycle Independent Mechanisms
Bibliographic record
Abstract
Pocket proteins (pRb, p107 and p130) are well studied in the role of regulating cell proliferation by controlling progression through the G1/S phase of the cell cycle. Increasing genetic and anatomical evidence suggests that these proteins also control early differentiation and even later stages of cell maturation including neural migration. However, the multifaceted functions of pocket proteins in the regulation of cell proliferation and cell death has complicated our interpretation of their role during development. As a result, the mechanisms through which pocket proteins regulate neuronal migration and neural maturation remain unknown. Using a pRb and p107 double knock out model, we show that a population of upper layer cortical neurons fails to pass through the intermediate zone into the cortical plate. Importantly, these neurons are born at the appropriate time and have exited the cell cycle. In addition, the role of pocket proteins in radial migration is independent cell death, since this migration defect cannot be rescued by eliminating ectopic cell death through Bax deletion. We also show a novel role of pRb and p107 in development of the dorsal midline and guidance of callosal axons. In the absence of pRb and p107, the structures of the commissural plate are highly disorganized and the callosal axons fail to cross the midline. We identify primary defects in axon extension and expression of multiple guidance cues, which can be observed prior to the disorganization of the midline axon guidance structures. Through the use of in vitro cortical explants and in utero electroporation, we identify defects in the rate of axon extension and directional guidance independent from the midline. In addition, protein levels of Netrin and Neuropilin-1 are decreased in the absence of pRb and p107, which could mediate the function of pocket proteins in guiding callosal axons. Indeed, we identify a previously undescribed population of Netrin expressing cells in the cingulate cortex of control embryos which is lost in the pRb/p107 deficient littermates. We propose that these cells play a significant role in callosal axon guidance during normal development. The results presented in this dissertation define multiple novel roles of pRb and p107 in the regulation of radial migration and axon guidance, independent from the role of these pocket proteins in cell death and proliferation.
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".