545. DEFICIENCY OF <i>TBX1</i>, A GENE ENCODED IN 22Q11.2 COPY NUMBER VARIATION, IMPAIRS SOCIAL AND COGNITIVE BEHAVIORS BY ALTERING BRAIN SHAPE AND NEONATAL STEM CELLS
Bibliographic record
Abstract
Abstract Background Copy number variants (CNVs) at human chromosome 22q11.2 are associated with social and cognitive deficits and psychiatric disorders, but mechanisms underlying this association are still poorly understood. Our group has identified Tbx1 as a 22q11.2 driver gene for distinct social and cognitive deficits. Aims & Objectives We have characterized the impacts of constitutive and post-embryonic Tbx1 deficiency on molecular, cellular, structural, and behavioral functions. Method TBX1 protein is expressed at high levels in the embryonic mouse brain. To evaluate the role of Tbx1 on the embryonic generation of neurons and subsequent brain volume's regional volumes, we applied volumetric MRI to the whole brains of adult constitutive Tbx1 heterozygous mice. Moreover, we measured cellular excitability using two-photon imaging of Ca2+ influx and determined the expression of genes for inhibitory and excitatory transmission by scRNA-seq. In the post-embryonic mouse brain, TBX1 remains enriched in neonatal and adult stem cells. To conditionally initiate Tbx1 heterozygosity in post-embryonic stem cells, we developed nestinCreERT;Tbx1flox/+ mice and treated them with Tamoxifen at postnatal days 1 to 5 (P1-5) or postnatal days 21 to 25 (P21-25). These mice were tested for affiliative social interaction and working memory/cognitive flexibility 1 month later. Stem cells of neonatal P0 hippocampus of C57BL/6J pups were cultured to evaluate the role of Tbx1 in the proliferation and cell cycle of neonatal stem cells. The target genes of TBX1 in proliferating neonatal stem cells were identified by ChIP-seq and validated by ChIP-PCR. One identified gene was validated by Tbx1 knockdown and deletion and mutation of its promoter region. Results Constitutive Tbx1 heterozygosity reduced the volumes of the anterior and posterior amygdala and surrounding cortical regions, including the amygdalopiriform transition area, and impaired social incentive learning in an amygdala-dependent task. The amygdalopiriform transition area had lower levels of cellular excitability in acute slices. The expression of Tbr1, Rorb, and Nfia, which our ChIP-seq analysis identified as TBX1's target genes, were reduced in inhibitory neurons of the amygdala of Tbx1 heterozygous mice. Conditional Tbx1 heterozygosity initiated in neonatal, but not postnatal, stem cells impaired post-pubertal social interaction and working memory/cognitive flexibility. Tbx1 deficiency in neonatal stem cells in vitro delayed their proliferation and cell cycle transition from G0/G1 to S phase. ChIP-seq identified TBX1 binding sites in the enhances/promoters of more than 1,000 genes implicated in adult neurogenesis, neurodevelopmental disorders, and myelin formation. Among them, TBX1 regulated the expression and transcriptional activity of PTEN in neonatal stem cells. Segmental deletions and point mutations of the Pten promoter identified a 35bp region as a critical sequence. Discussion & Conclusions Our data suggest that 1) constitutive Tbx1 deficiency reduces the volumes of the amygdala complex, down-regulates target genes there, and reduces neuronal excitability in the amygdalopiriform transition area and 2) post-embryonic Tbx1 deficiency reduces the rate of proliferation of neonatal stem cells by delaying their cell cycle transition from G0/G1 to S phase and alters the expression of many target genes involved in neurodevelopmental disorders, including Pten.
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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 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.012 | 0.002 |
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".