UBE3C links ubiquitin signaling to epitranscriptomic control of cortical neurogenesis

2025 · doi:10.1101/2025.04.09.646620
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UBE3C regulates cortical neurogenesis and glial fate by linking ubiquitin signaling to m6A epitranscriptomic control, impacting cell cycle exit and cortical lamination.

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⚙ AI-generated deep summary by claude@2026-07, 2026-07-14 · read from full text ⓘ

The study investigated how the ubiquitin ligase UBE3C, implicated in a neurodevelopmental disorder, regulates murine cerebral cortical development and human brain organoid cell fate. Using UBE3C loss-of-function models and genetic complementation, the authors found that UBE3C loss favors neurogenesis over glial fate, alters autoubiquitination for disease-associated mutations, and disrupts cortical lamination; proteomic profiling identified Cbll1 as a UBE3C substrate and showed the UBE3C–Cbll1 axis drives m6A RNA methylation. They further reported that hyperactivation of m6A writers in UBE3C-deficient neural progenitors impairs cell cycle exit, with a cell-cycle defect reportedly reversible in vivo using the METTL3 inhibitor STM2457. The paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

ABSTRACT Neurological conditions are the leading cause of ill health worldwide. Here, we show that the neurodevelopmental disorder-associated ubiquitin ligase UBE3C regulates the cellular composition of the murine cerebral cortex and human brain organoids, with its loss favoring neurogenesis and suppressing glial fate. Using genetic complementation, we demonstrate that disease-associated UBE3C mutations alter its autoubiquitination activity and disrupt cortical lamination. Proteomic profiling of UBE3C -deficient forebrains and organoids identifies Cbll1 as a UBE3C substrate, and we show that the UBE3C-Cbll1 duo drives N 6 -methyladenosine (m6A) mRNA methylation. Hyperactivation of m6A writers in UBE3C -deficient neural progenitors impairs cell cycle exit, a defect reversible in vivo by the METTL3 inhibitor STM2457. Our findings uncover an epiproteomic mechanism controlling m6A-mediated gene expression and define a regulatory axis linking ubiquitin signaling to epitranscriptomic control of neural fate. This work provides a mechanistic framework for understanding neurodevelopmental disorders and highlights potential therapeutic strategies.
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UBE3C links ubiquitin signaling to epitranscriptomic control of cortical neurogenesis ABSTRACT Neurological conditions are the leading cause of ill health worldwide. Here, we show that the neurodevelopmental disorder-associated ubiquitin ligase UBE3C regulates the cellular composition of the murine cerebral cortex and human brain organoids, with its loss favoring neurogenesis and suppressing glial fate. Using genetic complementation, we demonstrate that disease-associated UBE3C mutations alter its autoubiquitination activity and disrupt cortical lamination. Proteomic profiling of UBE3C-deficient forebrains and organoids identifies Cbll1 as a UBE3C substrate, and we show that the UBE3C-Cbll1 duo drives N6-methyladenosine (m6A) mRNA methylation. Hyperactivation of m6A writers in UBE3C-deficient neural progenitors impairs cell cycle exit, a defect reversible in vivo by the METTL3 inhibitor STM2457. Our findings uncover an epiproteomic mechanism controlling m6A-mediated gene expression and define a regulatory axis linking ubiquitin signaling to epitranscriptomic control of neural fate. This work provides a mechanistic framework for understanding neurodevelopmental disorders and highlights potential therapeutic strategies. Competing Interest Statement The authors have declared no competing interest. Footnotes ↵A Senior authors Change of the title; acknowledgement of the funding support for the manuscript. Funder Information Declared Subject Area - Biochemistry (17697) - Bioengineering (13895) - Bioinformatics (41953) - Biophysics (21456) - Cancer Biology (18595) - Cell Biology (25521) - Clinical Trials (138) - Developmental Biology (13381) - Ecology (19903) - Epidemiology (2067) - Evolutionary Biology (24323) - Genetics (15612) - Genomics (22511) - Immunology (17738) - Microbiology (40401) - Molecular Biology (17184) - Neuroscience (88623) - Paleontology (667) - Pathology (2833) - Pharmacology and Toxicology (4825) - Physiology (7644) - Plant Biology (15158) - Synthetic Biology (4296) - Systems Biology (9825) - Zoology (2271)

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