Biology subjects

Bergamasco, M.

Publications and source records attributed to Bergamasco, M..

2 recordsLinked to original sources

bioRxiv2026

FBXW11 Activity Regulates Radial Glial Expansion in Human Cerebral Organoids

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.

neuroscience↗

bioRxiv2023

Trabid patient mutations impede the axonal trafficking of adenomatous polyposis coli to disrupt neurite growth

Trabid/ZRANB1 missense mutations have been identified in children diagnosed with a range of congenital disorders including reduced brain size, but how Trabid regulates neurodevelopment is not understood. We have characterised these patient mutations in cells and mice to identify a key role for Trabid in the regulation of neurite growth. One of the patient mutations flanked the catalytic cysteine of Trabid and its deubiquitylating (DUB) activity was abrogated. The second variant retained DUB activity, but failed to bind STRIPAK, a large multiprotein assembly implicated in cytoskeleton organisation and neural development. Trabid/ZRANB1 knock-in mice harbouring either of these patient mutations exhibited reduced neuronal and glial cell densities in the brain and a motor deficit consistent with fewer dopaminergic neurons and projections. Mechanistically, both DUB-impaired and STRIPAK-binding-deficient Trabid variants impeded the trafficking of adenomatous polyposis coli (APC) to microtubule plus-ends. Consequently, the formation of neuronal growth cones and the trajectory of neurite outgrowth from mutant midbrain progenitors were severely compromised. We propose that STRIPAK recruits Trabid to deubiquitylate APC, and that in cells with mutant Trabid, APC becomes hyperubiquitylated and mislocalised causing impaired organisation of the cytoskeleton that underlie the neuronal and developmental phenotypes.

cell biology↗