FBXW11 Activity Regulates Radial Glial Expansion in Human Cerebral Organoids
- 1Dr. John and Anne Chong Lab for Functional Genomics, Charles Perkins Centre and School of Life and Environmental Sciences, The University of Sydney, Sydney, New
Abstract
Human brain development depends on tightly coordinated gene-regulatory programs and the emergence of complex tissue architecture, making large scale functional interrogation difficult using conventional screen models. To overcome this challenge, we used a pooled CRISPR screening approach. Guided by neuro-specific whole-genome screens in Drosophila, we tested 129 poorly characterised human orthologs and found 8 that modify cerebral organoid development. Candidates were validated using individual CRISPR knockouts and mosaic competition assays. Among these candidates we describe FBXW11, a substrate-recognition component of the SCF E3 ubiquitin ligase complex, as a potent negative regulator of cerebral organoid expansion. FBXW11 loss increases radial glial abundance, expands ventricular-like domains, and impairs neuronal maturation. Mechanistically, FBXW11 associates with {beta}-catenin and alters WNT signalling. FBXW11 mutations cause the autosomal-dominant Mendelian syndrome Neurodevelopmental, Jaw, Eye and Digital syndrome (NEDJED), and we found that disease-associated variants mapped preferentially to WD40 substrate-binding repeats and {beta}-catenin contact regions, linking impaired substrate recognition to neurodevelopmental disease. Together, these findings identify FBXW11 as a conserved negative regulator of {beta}-catenin-dependent radial glial expansion and neuronal maturation during human cerebral brain development.
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BibTeX
@misc{moreno2026fbxw11,
title = {{FBXW11 Activity Regulates Radial Glial Expansion in Human Cerebral Organoids}},
author = {C. L. Moreno and H. King and S. Trabish and M. Thijs and D. Beck and M. Bergamasco and T. Y. D'Araujo and T. J. Mosca and R. Weatheritt and G. G. Neely},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.20.746070},
url = {https://www.biorxiv.org/content/10.64898/2026.08.20.746070v2},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - FBXW11 Activity Regulates Radial Glial Expansion in Human Cerebral Organoids
AU - C. L. Moreno
AU - H. King
AU - S. Trabish
AU - M. Thijs
AU - D. Beck
AU - M. Bergamasco
AU - T. Y. D'Araujo
AU - T. J. Mosca
AU - R. Weatheritt
AU - G. G. Neely
PY - 2026
DA - 2026/08/20
PB - bioRxiv
DO - 10.64898/2026.08.20.746070
UR - https://www.biorxiv.org/content/10.64898/2026.08.20.746070v2
AB - Human brain development depends on tightly coordinated gene-regulatory programs and the emergence of complex tissue architecture, making large scale functional interrogation difficult using conventional screen models. To overcome this challenge, we used a pooled CRISPR screening approach. Guided by neuro-specific whole-genome screens in Drosophila, we tested 129 poorly characterised human orthologs and found 8 that modify cerebral organoid development. Candidates were validated using individual CRISPR knockouts and mosaic competition assays. Among these candidates we describe FBXW11, a substrate-recognition component of the SCF E3 ubiquitin ligase complex, as a potent negative regulator of cerebral organoid expansion. FBXW11 loss increases radial glial abundance, expands ventricular-like domains, and impairs neuronal maturation. Mechanistically, FBXW11 associates with {beta}-catenin and alters WNT signalling. FBXW11 mutations cause the autosomal-dominant Mendelian syndrome Neurodevelopmental, Jaw, Eye and Digital syndrome (NEDJED), and we found that disease-associated variants mapped preferentially to WD40 substrate-binding repeats and {beta}-catenin contact regions, linking impaired substrate recognition to neurodevelopmental disease. Together, these findings identify FBXW11 as a conserved negative regulator of {beta}-catenin-dependent radial glial expansion and neuronal maturation during human cerebral brain development.
ER -