Rodrigo L. Borges, Gretter González-Blanco, Harikumar Arigela, Yingyu Huang, Lucas D. Caeiro, Nikolai Fattakhov, Stefano Lepore, Liliana Garcia-Martinez, Matea Maurice, Pushti D. Mehta, Emily J. Park, Kailynn MacGillivray, Jevithen Nehru, Matthew Hoi Kin Chau, Maria C Robayo, Clemer Abad, Alicia Bilbao-Martinez, Fabiola Monteiro, Xi Luo, Song Tan, Daniel Bilbao, Simone Sidoli, Bruno Di Stefano, Katherina Walz, Arneet L. Saltzman, Ramiro E. Verdún, Ramin Shiekhattar, Lluís Morey
The prevalence of neurodevelopmental disorders (NDDs) in children is increasing, yet their underlying causes remain largely unknown. We identified heterozygous mutations in the Polycomb repressive complex 1 (PRC1) E3 ligases RING1 and RNF2 in individuals with NDDs and revealed distinct mechanisms by which they compromise PRC1 activity. We developed cellular and mouse models carrying the Ring1b R70H variant, which disrupts PRC1/PRC2 recruitment balance and mis-regulates Polycomb target genes. Allele-specific profiling showed that Ring1b R70H preferentially assembles into canonical PRC1 (cPRC1) via the intrinsically disordered region (IDR) of Pcgf2, reducing variant PRC1 (vPRC1) and PRC2.1 binding to chromatin. In Rnf2 WT/R70H neuroprecursors, Polycomb complexes aberrantly suppress Wnt signaling, diverting neuroprecursors to non-neuronal lineages and halting neurogenesis. Rnf2 R70H/R70H mice are perinatally lethal, while heterozygotes exhibit altered axonal organization, hippocampal and medial prefrontal cortex (mPFC) neuronal imbalances, reduced sociability, and increased anxiety. Our findings reveal an epigenetic mechanism essential for neurodevelopmental integrity and brain function and demonstrate how mutations in Rnf2 disrupt PRC1 occupancy at chromatin, contributing to NDDs.