Meis1 isoform diversity orchestrates neural progenitor differentiation by regulating ATOH1 degradation at distinct subcellular compartments

PLoS Biol. 2026 Jul 13;24(7):e3003897. doi: 10.1371/journal.pbio.3003897. Online ahead of print.

ABSTRACT

The development of the complex nervous system is strictly controlled by diverse isoforms produced from individual genes, but the underlying machinery remains unclear. Our long-read cDNA sequencing of mouse cerebellar granule cell progenitors (GCPs) identifies more than 700 genes with high isoform diversity. One such gene, Meis1, produces MEIS1-FL and MEIS1-HdL isoforms, which include and lack the homeodomain, respectively. Our previous study showed that MEIS1-FL localizes to nuclei and promotes ATOH1 protein degradation through transcriptional regulation, thereby promoting GCP differentiation. In contrast, our in vivo electroporation experiments in the postnatal mouse cerebellum show that MEIS1-HdL inhibits GCP differentiation. MEIS1-HdL localizes in the cytoplasm and inhibits the degradation of ATOH1 mediated by CUL3, which is a newly identified E3 ligase for ATOH1. MEIS1-HdL enhances the binding of the COP9 signalosome to CUL3, which suppresses ATOH1 polyubiquitination. This study demonstrates that functionally antagonistic isoforms derived from a single gene cleverly control neural progenitor differentiation.

PMID:42441717 | DOI:10.1371/journal.pbio.3003897