Psmd13, a proteosome regulatory subunit for co-transcriptional miR-29a processing during neurogenesis

miR-29a plays a critical role in neuronal development and is associated with neurodegenerative diseases, but its regulatory mechanisms remain unclear. To identify genes that influence miR-29a expression, we utilized the genetically diverse Collaborative Cross (CC) mouse strains and conducted expression profiling and Quantitative Trait Loci (QTL) analysis. A significant QTL on chromosome 7 was identified, and ten candidate genes were mapped within this region. RNAi-mediated knockdown experiments revealed that Psmd13 and Nap1l4 significantly increased miR-29a expression, implicating these genes as upstream regulators. Further investigation in mouse neural precursor cells (mNPCs) demonstrated that Psmd13 knockdown enhanced neuronal differentiation, as indicated by increased βIII-tubulin-positive cells, and miR-29a inhibition also promoted this process. Co-immunoprecipitation experiments showed that Psmd13 interacts with Dicer, modulating miR-29a levels through a differentiation-dependent mechanism. Chromatin immunoprecipitation sequencing (ChIP-seq) revealed co-binding of Psmd13 and Dicer at key genomic loci, including miR-29a, influencing chromatin accessibility and transcriptional regulation. Notably, proteasome inhibition using MG132 decreased Psmd13 and Dicer levels, leading to downregulation of miR-29a and impaired neuronal differentiation. These findings suggest that Psmd13 and Dicer coordinate to regulate miR-29a biogenesis and neuronal differentiation, highlighting the proteasome's essential role in maintaining neurodevelopmental homeostasis.