Exosc9-KO Mouse

Exosc9, also known as exosome complex component RRP45, is a component of the RNA exosome complex. The RNA exosome is crucial for the correct processing and degradation of numerous RNAs, thus playing a vital role in regulating gene expression and various biological processes [5,6,7].

In cancer cells, EXOSC9 depletion attenuates growth and survival under stress conditions, decreases P-body formation (messenger ribonucleoprotein particles required for stress adaptation), and reduces tumorigenicity in an RNA-binding motif-dependent manner. Database analyses also show that higher EXOSC9 activity is correlated with poorer prognosis in some cancer patients [1]. In endocrine therapy-resistant hormone receptor-positive breast cancer cells, elevated Exosc9 drives cell growth by degrading lncRNA TERRA, which impacts telomeric integrity and DNA damage response, and may serve as a biomarker for predicting response to PARP inhibitors [2].

In addition, mutations in EXOSC9 are associated with pontocerebellar hypoplasia type 1D, a neurodegenerative disorder characterized by cerebellar atrophy, spinal motor neuropathy, and other neurological features. In zebrafish models, knockdown or mutagenesis of exosc9 recapitulates aspects of the human phenotype, with defects in cerebellar and motor neuron development [3,4,6]. RNA sequencing in human cells with EXOSC9 down-regulation shows changes in genes involved in neuronal development and p53-dependent signalling, providing insights into the pathogenesis of exosome-related disorders [7].

In conclusion, Exosc9 is essential for RNA processing and degradation through its role in the RNA exosome complex. Its functions have significant implications in cancer, especially in stress adaptation and tumorigenicity, as well as in neurodegenerative diseases such as pontocerebellar hypoplasia type 1D. Studies using animal models like zebrafish have been valuable in understanding the role of Exosc9 in these disease conditions.