Autism spectrum disorder (ASD) is a major neurodevelopmental disorder, yet despite its prevalence and severity, the substantial genetic heterogeneity of ASD (>700 associated genes) has been a major impediment to the development of therapeutic strategies. While treating disorders such as ASD one gene at a time is currently not viable, progress has recently been achieved by targeting points of convergence within risk-gene networks. In this regard, the team headed by Michael Piper’s laboratory has identified the X-linked ubiquitin specific protease 9 (USP9X) as causative factor for intellectual disability (ID), including ASD, in both males and heterozygous females. Their preliminary data reveal that USP9X, a deubiquitinating enzyme, is an upstream regulator of an interactome significantly enriched in ID-associated genes, placing USP9X at the hub of an ID gene/protein network. Crucially, the team has developed a unique mouse model in which conditional deletion of USP9X from the brain phenocopies structural brain abnormalities reported in individuals with USP9X-associated ID. Moreover, the group finds that over 90 percent of their USP9X-associated ID cohort exhibits ASD, further emphasizing this gene as a key nexus point.
Piper now proposes to test the mechanism by which mutations in USP9X lead to ID. His laboratory’s preliminary data suggest that neural stem cell proliferation and neuronal maturation are abnormal in the absence of USP9X. Piper’s team will now develop a conditional mouse line in which USP9X is ablated specifically from the cerebral cortex. This model will be used to further assess effects on cortical development in vivo and to assess the functional consequences of abnormal cortical development using behavioral paradigms. This animal model will also allow Piper to model the cell-autonomous effect of human USP9X mutations within the rodent brain. Collectively, these studies will provide significant insights into USP9X mutations and the development of ASD. Ultimately, Piper expects that this work will provide relevant insights into how ASD develops, information that is crucial for developing strategies aimed at preventing and treating this disorder.