Defective Neurogenesis in Lowe Syndrome is Caused by Mitochondria Loss and Cilia-related Sonic Hedgehog Defects
Bibliographic record
Abstract
Human brain development requires tight coordination of metabolic and signaling pathways. Lowe syndrome (LS) is a recessive X-linked disorder characterized by proximal tubular renal disease, congenital cataracts, glaucoma, and neurodevelopmental delays. While LS results from mutations in the OCRL gene, which encodes an inositol polyphosphate 5-phosphatase, the cellular mechanisms driving neuronal dysfunction remain poorly understood. In this study, using patient-derived iPSC neurons, an OCRL knockout mouse model, and an independent zebrafish OCRL-deficient model, we identified mitochondrial dysfunction as a conserved phenotype of OCRL loss across species. Collectively, our findings showed that OCRL deficiency leads to reduced mitochondrial activity, decreased mtDNA levels, reduced mitochondrial content (TOM20), and increased oxidative stress. We further showed that OCRL-deficient neural cells exhibited an altered balance of neuronal versus astrocytic differentiation, rather than a defect in neurogenesis. Additionally, we observed impaired Sonic Hedgehog (Shh) signaling and ciliary homeostasis. Thus, we propose that mitochondrial dysfunction-induced oxidative stress acts as a central mediator linking OCRL loss to altered cell fate and disrupted Shh signaling, providing a unifying framework for these phenotypes.
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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) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 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 | 0.002 |
| Research integrity | 0.001 | 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".