During corticogenesis, excitatory neurons are born from neural progenitor cells (NPCs). Cortical neuron subtypes are sequentially differentiated from a common multipotent NPC, through progressive lineage restriction. Dynamic changes in chromatin states are predicted to underlie the transcriptional plasticity required to restrict NPC fate. This observation is bolstered by the disproportionate number of de novo dominant pathogenic variants in chromatin modifying genes recently identified in association with autism spectrum disorder (ASD).
De novo dominant pathogenic variants in the Polycomb group (PcG) protein ASXL3 (additional sex combs like 3) have been identified as the genetic basis of a set of neurodevelopmental disorders with syndromic features of ASD1. ASXL3 is a component of the Polycomb repressive deubiquitinase complex (PR-DUB), which deubiqutinates histone H2A lysine 119 mono-ubiquitination (H2AUb1). Stephanie Bielas’s laboratory previously demonstrated that pathogenic ASXL3 variants alter the genome-wide H2AUb1 levels and affect transcriptional regulation in cells derived from individuals with these variants2. Further, new preliminary findings suggest that the genetically engineered Asxl3 null mouse model exhibits disrupted levels of genome-wide histone H2AUb1 and cortical lamination defects. Based on these findings, Bielas hypothesizes that ASXL3-dependent deubiquitination activity plays a critical role in specifying NPC transcriptional programs that restrict NPC multipotency and contribute to neuronal diversity of the cortex.
Using this Asxl3 knockout mouse model, state-of-the-art genetic tools and molecular profiling approaches, Bielas’s laboratory will investigate how developmentally dynamic genome-wide modifications in histone H2A ubiquitination influence the transcriptional profile and fate restriction of NPCs during corticogenesis. By correlating NPC transcriptional profiling with outcomes of cortical neuron differentiation, the researchers will gain direct mechanistic insights into NPC fate restriction and cortical neuronal subtypes altered by mutations in Asxl3. These efforts should unveil mechanisms of dysregulation that lead to ASD pathology and inspire new strategies for therapeutic intervention.