Ubb, the polyubiquitin gene, encodes ubiquitin, a highly conserved eukaryotic protein crucial for cellular signal transduction, differentiation, and proteolysis [3,4]. Ubiquitin tags damaged and redundant proteins for removal by the ubiquitin-proteasome system (UPS), thus maintaining cellular proteostasis [2].

Disruption of the Ubb gene in mouse models leads to various neural-related phenotypes. In Ubb knockout (KO) mice, retinal degeneration occurs, as indicated by a decreased thickness of the outer nuclear layer of the retina, reduced rhodopsin levels, and increased glial fibrillary acidic protein levels [3]. Also, Ubb KO neural stem cells (NSCs) show decreased self-renewal capacity, with reduced proliferation markers and thinner ventricular zones in embryonic brains [4]. In clear cell renal cell carcinoma (ccRCC), UBB is downregulated, which affects patient survival and potentiates SP1/VEGFA-dependent angiogenesis. DNA methyltransferase 3 alpha (DNMT3A) epigenetically inhibits UBB transcription, and an unharmonious UBB/VEGFA ratio mediates pazopanib resistance [1].

In summary, Ubb is essential for maintaining normal neural functions, including the survival of photoreceptor cells in the retina and the self-renewal of NSCs. In disease conditions, such as ccRCC, Ubb's dysregulation plays a role in angiogenesis and drug resistance. The study of Ubb knockout mouse models has been instrumental in revealing its functions in normal biology and disease-related processes.