hnRNPC regulates cerebellar development via Mtf2 alternative splicing

Precise regulation of alternative splicing is essential for neural development, yet how alternative splicing is integrated with developmental gene expression programs during cerebellar development remains poorly understood. Here, we identify the RNA-binding protein hnRNPC as a key regulator of cerebellar progenitor expansion through a splicing-dependent mechanism. Conditional deletion of Hnrnpc in neural progenitors caused severe cerebellar hypoplasia characterized by impaired granule cell progenitor proliferation and increased apoptosis. We identified Mtf2 as a critical downstream target of hnRNPC. Mechanistically, hnRNPC suppresses the inclusion of a cryptic exon in Mtf2 transcripts, thereby maintaining functional MTF2 expression. MTF2, in turn, promotes developmental gene expression required for cerebellar progenitor expansion. Consistent with this mechanism, loss of hnRNPC disrupted Mtf2 splicing and reduced MTF2 expression both in vivo and in primary granule cell progenitor cultures. Moreover, MTF2 overexpression partially restored proliferation and reduced apoptosis following hnRNPC depletion, establishing MTF2 as a critical downstream effector of hnRNPC. Importantly, granule cell progenitor-specific deletion of Hnrnpc recapitulated the developmental and molecular defects observed in neural progenitor-specific knockout mice and resulted in motor coordination deficits, further validating the physiological relevance of the hnRNPC–MTF2 regulatory axis in cerebellar development. Together, our findings demonstrate that hnRNPC-dependent alternative splicing of Mtf2 links post-transcriptional RNA processing to developmental gene expression programs during cerebellar development.