Description
- Abstract:
- Mutations in the transcription factor SOX9 cause Campomelic Dysplasia, a genetic disorder marked by profound defects in embryonic bone and cartilage development. Severe neonatal presentations frequently involve cardiopulmonary compromise and early death, suggesting that SOX9 also contributes to extraskeletal developmental processes essential for compatibility with life. We reasoned that additional SOX9-dependent roles in vital organ systems may be underrecognized because in-utero lethality precludes their detailed study. Focusing on the brain, we hypothesized that loss of the zebrafish SOX9 co-orthologs, sox9a and sox9b, would be associated with persistent cerebrovascular abnormalities in zebrafish embryos. To test this, the lab generated sox9a/b double-mutant zebrafish carrying vascular and erythrocyte transgenic reporters (Tg(kdrl:GFP;gata1a:DsRed) to visualize the developing neurovasculature by confocal microscopy. Confocal images from wild-type and mutant embryos at 72 hpf were manually annotated for deviations from expected vascular anatomy. We then developed a reproducible quantification workflow and performed statistical comparisons between the genotypes. At 72 hpf, sox9a/b double-mutants exhibited significant cerebrovascular defects relative to controls. More than half lacked a mesencephalic vein or had a shortened mesencephalic vein (p = 0.001 and p = 0.0004, respectively). Double-mutants also showed a higher incidence of intracerebral hemorrhage (p = 0.017), aberrant midline crossing of the anterior cerebral veins (p = 0.037), and central artery malformations, including reduced perfusion and stenosis (p = 0.024 and p = 0.033, respectively). These findings are consistent with a role for sox9a and sox9b in establishing functional cerebral vasculature during early development. Additionally, they further raise neurovascular dysgenesis as a potential contributor to early lethality in SOX9-associated disorders and provide a starting framework for future, more in-depth, mechanistic studies of SOX9 function in neural development. (Funding: NIH 1R01ES030109-01A1 and T35 HL094308.)
- Notes:
- Scholarly concentration: Non-Scholarly Concentrator
Access Conditions
- Use and Reproduction
- All rights reserved
- Rights
- In Copyright
- Restrictions on Use
- All Rights Reserved
Citation
Guerrero, Alisha, Harrison, Riley, Albro, Katrina, et al.,
"Cerebrovascular Malformations in sox9a/b Double-Mutant Zebrafish Embryos Suggest a Role for SOX9 Orthologs in Early Neurovascular Development"
(2025).
Warren Alpert Medical School Academic Symposium.
Brown Digital Repository. Brown University Library.
https://repository.library.brown.edu/studio/item/bdr:uk7z826k/
Relations
Collection:
-
Warren Alpert Medical School Academic Symposium
The Warren Alpert Medical School Academic Symposium is an annual event at Warren Alpert Medical School of Brown University that provides Year II medical students a venue to present their summer research in a poster format. Participation in the Symposium …...