Dépôt numérique

Craniofacial dysmorphism in CHARGE syndrome due to dysregulation of serotonin receptor HTR2B

Breuer, Maximillian, Jamadagni, Priyanka et Patten, Shunmoogum A. . Craniofacial dysmorphism in CHARGE syndrome due to dysregulation of serotonin receptor HTR2B In: 11e European Zebrafish Meeting, 26-27 October 2020, virtuel.

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CHARGE syndrome is a severe multisystemic developmental disorder that is most commonly caused by mutations in the ATP-dependent chromatin remodelling enzyme CHD7. To understand the function of CHD7, we generated a chd7 mutant in zebrafish by CRISPR/Cas9 mediated mutagenesis. This model has proven highly efficient in replicating the characteristics observed in CHARGE syndrome including craniofacial defects. Using an unbiased transcriptomic analysis (RNA-Seq), we identified a significant downregulation of the 5-hydroxytryptamine receptor 2b (Htr2b) in these chd7 mutant zebrafish. Interestingly, this member of the serotonin receptor family is closely associated with behavioral defects including impulsiveness and aggressiveness, as well as developmental defects in heart and jaw development, which are characteristics observed in CHARGE syndrome. To gain more insights in the role of htr2b in CHARGE syndrome pathogenesis, we assessed its function further in zebrafish. We found that htr2b is expressed in the branchial arches, giving rise to the jaw, via whole-mount in situ hybridization. Htr2b inhibition via the specific inhibitor RS-12744 partially mimics the morphological phenotypes. More specifically, the inhibition of Htr2b results in defective development of the palatoquadrate in the jaw as determined by alcian blue and calcein staining, with high similarity to the morphology observed in chd7 mutants. To further understand the mechanism involved we generated htr2b and htr2b/chd7 mutants to determine its role in the defective craniofacial development that is often observed in CHARGE syndrome patients. First results indicate a high dependency on Htr2b for successful palatoquadrate development, which may underlie the craniofacial phenotype in CHARGE syndrome. Altogether, our data show an implication of dysregulated HTR2B functions upon loss of function of CHD7 in CHARGE syndrome pathogenesis and suggest that HTR2B may serve as a potential therapeutic target.

Type de document: Document issu d'une conférence ou d'un atelier
Informations complémentaires: Affiche scientifique P043
Mots-clés libres: -
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 14 juill. 2021 15:42
Dernière modification: 14 juill. 2021 15:42
URI: https://espace.inrs.ca/id/eprint/11856

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