Rnf220, also known as Ring finger protein 220, is an evolutionarily conserved RING-type ubiquitin E3 ligase. It plays crucial roles in multiple cellular processes, participating in various signaling pathways such as Shh, Wnt, and IFN-STAT1 signaling, which are essential for vertebrate embryo development, cell differentiation, and immune response [5].

In mouse models, Rnf220 knockout specifically increases AMPAR protein levels, enhancing basal synaptic activity while impairing synaptic plasticity, and also altering learning and memory in forebrain-deficient mice, indicating its role in excitatory synaptic transmission [1]. Rnf220 depletion in oligodendrocyte lineage cells in mice impedes oligodendrocyte progenitor cell proliferation, differentiation, and (re)myelination, leading to learning and memory defects, highlighting its importance in oligodendroglial development [2]. Rnf220-deficient mice show down-regulation of IFN signaling and decreased expression of ISGs in response to infections, demonstrating its role in innate immune responses [3]. In Rnf220-deficient mice, the development of central NA neurons is affected as genes associated with LC-NA neurons are not properly maintained [4]. Nestin-Cre-mediated conditional knockout (Rnf220 Nestin CKO) mice show alterations in progenitor domains in the ventral VZ of the hindbrain, revealing its role in hindbrain dorsoventral patterning [6]. RNF220 +/ -; Ptch1 +/-mice have lower spontaneous medulloblastoma occurrence compared with Ptch1 +/-mice, suggesting its role in medulloblastoma progression [7]. Overexpression of RNF220 promotes the proliferation of AML cells in vitro [8].

In conclusion, Rnf220 is a multifunctional E3 ubiquitin ligase involved in neural development, immune response, and cancer progression. Gene knockout and conditional knockout mouse models have been instrumental in uncovering its role in excitatory synaptic transmission, oligodendroglial development, innate immune responses, central NA neuron development, hindbrain patterning, and cancer-related processes, providing insights into the underlying mechanisms of related diseases.