RNF220 is a RING-type E3 ubiquitin ligase with pleiotropic roles in neural development and disease. As an E3 ligase, RNF220 mediates polyubiquitination and proteasomal degradation of multiple substrates including WDR5, EED, and PDE10A 123. Independently of its canonical ligase activity, RNF220 stabilizes β-catenin through USP7-mediated deubiquitination, promoting Wnt signaling 2. During oligodendroglial development, RNF220 catalyzes K63-linked polyubiquitination of Olig1/2 transcription factors, promoting their stabilization and essential for myelination 4. RNF220 regulates Sonic hedgehog (Shh) signaling during cerebellar and hindbrain development through modulation of Gli proteins and epigenetic regulators 251. RNF220 loss inhibits neural stem cell proliferation while promoting neuronal differentiation 6. In cancer, RNF220 overexpression drives cisplatin resistance and immune evasion in bladder cancer through PDE10A degradation 3, and promotes Shh-medulloblastoma progression 7. Clinically, RNF220 mutations cause hypomyelinating leukodystrophy with ataxia, deafness, and cardiac dysfunction 4, while mutations cause small sperm head defects 8. RNF220 protein stability is regulated by RLIM and ZC4H2 5.