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bioRxiv · 10.64898/2026.01.18.700201

Asymmetric partition of the O-GlcNAcome in mitosis ensures binary cell fate decision

Chen, F.·Yu, H.·Zeng, W.·Wei, X.·Mao, S.·Lv, L.·Qin, H.·Liu, K.·Huang, H.·Zhang, Z.·Yao, X.·Yuan, K.
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Abstract

Many cellular components undergo biased segregation during stem cell division, but whether such order extends to the proteome has remained unknown. Using our real-time O-GlycoTracer, we find that O-GlcNAcylated proteins (the O-GlcNAcome) segregate asymmetrically during Drosophila neuroblast mitosis, predisposing the two daughters to distinct fates. The daughter that preserves stem cell identity inherits most of the O-GlcNAcome. This asymmetric partition requires putative O-GlcNAc readers, notably 14-3-3 proteins. We further identify the nuclear pore complex (NPC) as a major O-GlcNAc substrate in neuroblasts; Nup153, located in the nuclear basket, shows O-GlcNAc-dependent biased inheritance. Perturbing multiple steps in this segregation pathway disrupts neuroblast differentiation, reduces brain size, and causes adult learning deficits. These findings reveal a coordinated O-GlcNAc-driven mechanism for proteome-level asymmetric inheritance during neural stem cell division, with implications for neurodevelopmental disorders linked to OGT or 14-3-3 mutations.

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Chen, F., Yu, H., Zeng, W., Wei, X., Mao, S., Lv, L., Qin, H., Liu, K., Huang, H., Zhang, Z., Yao, X., Yuan, K.. 2026-01-20. Asymmetric partition of the O-GlcNAcome in mitosis ensures binary cell fate decision. https://doi.org/10.64898/2026.01.18.700201

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