RBFOX2, also known as RBM9, RTA, or HNRBP2, is an RNA-binding protein crucial for tissue-specific alternative splicing regulation and steroid receptor transcriptional activity [5]. It is involved in multiple biological processes such as cytoskeletal organization, focal adhesion formation, and cholesterol homeostasis, with its dysregulation linked to various diseases [1,3,7]. Genetic models, especially KO/CKO mouse models, have been instrumental in understanding its functions.

In pancreatic ductal adenocarcinoma (PDA), overexpression of RBFOX2 in a patient-derived xenograft metastatic PDA cell line reduced metastatic potential, while its depletion in primary pancreatic tumour cell lines increased it, suggesting it as a metastatic suppressor in PDA, potentially through regulating RHO GTPase pathways [1]. In myeloid leukaemia, down-regulation of RBFOX2 inhibited acute myeloid leukaemia cell survival/proliferation and promoted myeloid differentiation, indicating its importance in leukaemia maintenance [2]. In a mouse model of pancreatic cancer, down-regulation of RBFOX2 promoted pancreatic cancer progression and liver metastasis by regulating exon splicing events related to cytoskeletal remodeling [3]. In glioblastoma, FBXO7 stabilized Rbfox2 through ubiquitination, controlling its-mediated splicing of mesenchymal genes, contributing to mesenchymal transformation and chemoresistance [4]. In diabetes-induced cardiac hypertrophy, dysregulated Rbfox2 led to aberrant splicing of CaV1.2 calcium channel, and siRNA-mediated knockdown of Rbfox2 in neonatal rat ventricular myocytes induced cardiomyocyte hypertrophy [6]. Conditional deletion of Rbfox2 in embryonic mouse hearts caused defects in cardiac chamber and yolk sac vasculature formation, recapitulating features of hypoplastic left heart syndrome, likely through dysregulating alternative splicing networks affecting cell-ECM adhesion mediated by Rho GTPases [8].

In summary, RBFOX2 is essential for regulating alternative splicing in multiple biological processes. Its dysregulation is associated with various diseases including cancer, leukaemia, and diabetes-related cardiac hypertrophy. Studies using KO/CKO mouse models have significantly enhanced our understanding of how RBFOX2 contributes to these disease conditions, providing potential therapeutic targets for treatment.