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bioRxiv · 10.1101/2022.08.17.504235

Homeodomain-less MEIS1 suppresses CUL3-dependent ATOH1 degradation to regulate cerebellar granule cell development

Owa, T.·Shiraishi, R.·Adachi, T.·Miytashita, S.·Ichijo, K.·Nishioka, T.·Taya, S.·Kaibuchi, K.·Hoshino, M.
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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 identifies more than 700 genes with high isoform diversity in cerebellar granule cell progenitors (GCPs). 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 experiment in this study shows 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.

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Owa, T., Shiraishi, R., Adachi, T., Miytashita, S., Ichijo, K., Nishioka, T., Taya, S., Kaibuchi, K., Hoshino, M.. 2022-08-17. Homeodomain-less MEIS1 suppresses CUL3-dependent ATOH1 degradation to regulate cerebellar granule cell development. https://doi.org/10.1101/2022.08.17.504235

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