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This study reveals how two protein variants (isoforms) from the single Meis1 gene oppositely control the differentiation of neural progenitor cells in the developing mouse cerebellum. The MEIS1-FL isoform, located in cell nuclei, promotes differentiation by triggering degradation of the ATOH1 protein through gene regulation, while the MEIS1-HdL isoform, located in the cytoplasm, prevents differentiation by protecting ATOH1 from degradation by the CUL3 enzyme. Using long-read sequencing and genetic manipulation experiments, researchers demonstrated that these antagonistic isoforms provide precise control over when neural progenitors stop dividing and mature into neurons.
Why it matters
Understanding how single genes produce functionally opposite protein variants could help explain how complex developmental processes are fine-tuned and may inform future strategies for treating neurodevelopmental disorders or controlling cell differentiation in regenerative medicine applications.
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by Tomoo Owa, Toma Adachi, Ryo Shiraishi, Kentaro Ichijo, Kaiyuan Ji, Minami Mizuno, Kyoka Suyama, Kayo Nishitani, Ikuko Hasegawa, Masaki Sone, Daisuke Kawauchi, Tomoki Nishioka, Shinichiro Taya, Yutaka Suzuki, Kozo Kaibuchi, Satoshi Miyashita, Mikio Hoshino
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.