Psmc3-flox Mouse

Psmc3, also known as proteasome 26S subunit, ATPase, 3, encodes the AAA-ATPase proteasome subunit PSMC3/Rpt5. It is one of six AAA-ATPase proteasome subunits (PSMC1-6) crucial for the recognition, binding, unfolding, and translocation of protein substrates, which is essential for protein degradation by 26S proteasomes, thus maintaining protein homeostasis [1,3]. It is involved in pathways like RNA interference (RNAi) [2], and may play roles in neurodevelopment-related and other disease-associated pathways. Genetic models, such as knockout (KO) mouse models, are valuable for studying its functions.

In KO mouse models, both Psmc3-deficient mice died before implantation, showing defective blastocyst development, indicating its essential role in early embryogenesis [4]. In human studies, 15 de novo missense variants in PSMC3 were identified in 23 patients with autosomal dominant neurodevelopmental delay and intellectual disability. Expression of these variants in mouse neuronal cultures altered dendrite development, and deletion of the PSMC3 fly ortholog Rpt5 impaired reversal learning in fruit flies. These suggest Psmc3's role in neurodevelopment. Also, proteasome dysfunction due to PSMC3 variants led to proteotoxic stress, type I interferon production, and disrupted proteins controlling developmental and innate immune programs [1]. In addition, a unique deep intronic homozygous variant in PSMC3 in patients with severe deafness and early-onset cataracts caused proteotoxic stress, and zebrafish knockout of PSMC3 reproduced the human phenotype, indicating its role in inner ear, lens, and central nervous system development [3].

In conclusion, Psmc3 is essential for maintaining protein homeostasis, with a critical role in early embryogenesis, neurodevelopment, and the development of the inner ear, lens, and central nervous system. Studies using KO mouse models and other genetic models have provided insights into its functions in these biological processes and related disease conditions, such as neurodevelopmental disorders and neurosensory syndromes.