Kuriakose, D.; Morahan, G.; Xiao, Z.

miR-29a is essential for neuronal development and implicated in neurodegenerative diseases, yet its regulatory mechanisms remain poorly understood. To identify upstream regulators of miR-29a expression, we leveraged the genetically diverse Collaborative Cross (CC) mouse strains and performed expression profiling and Quantitative Trait Loci (QTL) analysis, identifying a significant QTL on chromosome 7. Among ten candidate genes, Psmd13 emerged as a key regulator, with RNAi-mediated knockdown in mouse neural precursor cells (mNPCs) leading to enhanced neuronal differentiation and increased miR-29a expression in the undifferentiated state but decreased expression upon differentiation. Co-immunoprecipitation assays revealed that Psmd13 interacts with Dicer, modulating miR-29a levels in a differentiation-dependent manner. Chromatin immunoprecipitation sequencing (ChIP-seq) demonstrated Psmd13-Dicer co-binding at genomic loci, including miR-29a, suggesting a role in chromatin accessibility and transcriptional regulation. Proteasome inhibition using MG132 reduced Psmd13 and Dicer levels, downregulating miR-29a and impairing neuronal differentiation. These findings indicate that differentiation dynamically alters miR-29a transcription through Psmd13-Dicer interactions.