“AHR Signaling in Neurovascular Development and Disease” - Jess Plavicki

“AHR Signaling in Neurovascular Development and Disease” Seminar: 

Jess Plavicki
Associate Professor and Vice Chair of Education
Department of Pathology and Laboratory Medicine, Brown University

SOX9 is a high mobility transcription factor that is dynamically expressed during organogenesis and also expressed in mature organ systems, including the central nervous system, the cardiovascular system, and the musculoskeletal system. Previous work from multiple groups has demonstrated that contaminant induced activation of the aryl hydrocarbon receptor (AHR), a ligand activated transcription factor, results in downregulation of sox9b, one of two zebrafish co-orthologues of SOX9. Data from our lab indicates that sox9a, the other SOX9 co-orthologue, is also a transcriptional target of the AHR signaling pathway. Mutations in human SOX9 result in campomelic dysplasia (CD), a rare genetic disorder characterized by multiple developmental defects including hydrocephalus, limb and jaw malformations, congenital cardiac defects, XY sex reversal, and underdeveloped lungs. CD is usually embryonic lethal and, as a result, the loss of function phenotypes observed in individuals who reach postnatal stages reflect only the phenotypes compatible with survival. We hypothesize that individuals with CD who have severe disruptions in brain and vascular development are likely to die in utero and, therefore, postulate that there are unidentified functions for SOX9 and its zebrafish co-orthologues in brain and vascular development. To identify novel developmental functions for sox9a and sox9b and to understand the health impacts of environmental contaminants that disrupt SOX9 function, we used CRISPR/Cas9 to create new sox9a and sox9b mutants. Preliminary data from single and double mutants suggest that zebrafish with mutations in sox9a and sox9b have impaired CNS angiogenesis, brain hemorrhages, ventriculomegaly, and disrupted neural network formation, which are all phenotypes observed with dioxin-induced AHR activation. Studies are underway to further characterize how loss of sox9a and sox9b affects glial-vascular interactions during embryonic brain development and to identify the molecular mechanism mediating our observed mutant phenotypes.