DISRUPTION OF NR2F1 DNA-BINDING ACTIVITY COMPROMISES CORTICAL DEVELOPMENT AND BRAIN INTEGRITY

Neurodevelopmental disorders (NDDs) are genetically heterogeneous conditions affecting cognition, social interaction, behavior, and motor function. Their complexity—marked by overlapping clinical features and limited access to human brain tissue—hampers research and treatment. However, evidence indicates many NDDs share core developmental pathways.
Our research focuses on Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS), a rare autosomal dominant NDD characterized by cognitive and visual impairment, autism spectrum traits, developmental delay, and epilepsy. BBSOAS arises from de novo deletions or loss-of-function variants in NR2F1, a nuclear receptor crucial for early cortical development. Using a Nr2f1-null mouse model, we showed that Nr2f1 regulates key neurodevelopmental processes, including neural progenitor proliferation and differentiation, neuronal migration and circuit formation.
However, classical loss-of-function models fail to capture clinical heterogeneity. Pathogenic variants include whole-gene deletions or missense mutations clustering in the DNA-binding domain (DBD) or in the ligand-binding domain (LBD), which differentially impair transcriptional regulation or cofactor interactions. To determine the underlying causes of BBSOAS, we generated patient-specific knock-in mouse models carrying DBD or LBD mutations. The DBD mutant exhibits a more severe phenotype, likely due to dominant-negative effects, including ventricular enlargement, hippocampal lesions, disrupted progenitor polarity, and reduced microglial numbers and activity. These changes are likely to compromise brain integrity and stiffness, with altered extracellular matrix and myelination.
Given microglia’s emerging role in maintaining tissue integrity and modulating neural progenitor activity, our findings suggest that microglial dysfunction contributes to defects in tissue organization and circuit assembly in BBSOAS, linking early microglial alterations to lasting neurodevelopmental outcomes.