Temporal dissection of Rai1 function reveals brain-derived neurotrophic factor as a potential therapeutic target for Smith–Magenis syndrome
Bibliographic record
Abstract
Haploinsufficiency of retinoic acid-induced 1 (RAI1) is responsible for Smith-Magenis syndrome (SMS), a childhood neurodevelopmental disorder associated with hyperphagia, obesity and autistic features. We previously showed that constitutive inactivation of one or both copies of Rai1 in the germline or developing brain induces SMS-like neurobehavioral deficits and obesity in mice. By contrast, the postnatal function of Rai1 is unclear. Here, we globally deleted one or both copies of Rai1 during two postnatal developmental windows by generating an inducible Rai1 knockout mouse model. We found that delayed Rai1 deletion at 3 or 8 weeks of age had no effect on neurobehavioral functions but resulted in adult-onset obesity and decreased expression of brain-derived neurotrophic factor (Bdnf) in the hypothalamus. Remarkably, genetic overexpression of human Bdnf in Rai1 heterozygous mice reversed SMS-like obesity, hyperphagia, metabolic syndrome-like features and hyposociability. Increasing Bdnf signaling in the paraventricular nucleus of the hypothalamus or the ventromedial nucleus of the hypothalamus was sufficient to mediate the anti-obesity effect. Our work identifies the function of Rai1 in different temporal windows after birth and provides in vivo evidence that increasing Bdnf signaling is therapeutically effective in a preclinical mouse model of SMS.
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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".