HMGN1 as a Mediator of Dysregulated Sonic Hedgehog Signaling and Autism Risk in Down Syndrome
Anna Moyer | Thyme Research Group | Jerome Lejeune Foundation Postdoctoral Fellowship
Down syndrome (DS) is caused by trisomy for human chromosome 21 and affects more than five million individuals worldwide. Autism spectrum disorder (ASD) is a common co-occurring condition in persons with DS. Because individuals with DS-ASD often present with deleterious behaviours, such as self-injurious behaviour, aggression, sleep disturbances, and feeding difficulties, identifying effective treatments for the behavioural sequelae of DS-ASD has the potential to improve quality of life for individuals with DS and their caregivers. However, recent research has focused on diagnosing DS-ASD and describing its behavioural profile. The underlying molecular mechanisms that contribute to DS-ASD risk remain unexplored. Other DS-associated phenotypes likely result from dysregulation of the Sonic hedgehog (Shh) signalling pathway, which is a critical developmental pathway. Because Shh signalling is required for the differentiation of serotonergic neurons and because the serotonergic system is implicated in the pathogenesis of ASD, we hypothesized that disruption of Shh could result in behavioural phenotypes relevant to ASD. To address this hypothesis, we will perturb Shh signalling in developing zebrafish and assess serotonergic neuron morphology, overall brain structure, brain activity, and behaviour. How trisomy 21 contributes to misregulation of Shh also merits further study. Based on a previous screen of chromosome 21 genes, we selected HMGN1 as a likely regulator of Shh. We will overexpress HMGN1 and explore its effects on Shh signalling, serotonergic neurons, behaviour, gene expression, and epigenetic modifications. Successful completion of this project will lay the foundation for drug screens relevant to DS-ASD and cognition in larval zebrafish models.
