RBM4, an RNA binding protein, is recognized for its role as a splicing regulator in various tissues, contributing to the diversity of proteins. In our study, we conducted a comprehensive examination of alternative splicing events potentially governed by RBM4, leveraging predictive RNA sequencing data including Rbfox2, Prpf40b and Add3. Notably, we identified differences in these splicing events across various time points and tissues. In addition to this, histological sections subjected to HE and Nissl staining revealed distinct phenotypes in plenty of tissues. In our observations, the Rbm4 knockout cerebellum exhibited a distinct foliation defect, particularly notable between lobules VI and VII. Moving to the cardiovascular system, we observed noteworthy disparities between the wildtype and Rbm4 double knockout mice. Specifically, there were marked differences in ventricular area and interventricular septum thickness. Shifting focus to skeletal muscle, the knockout mice displayed a notably lower average fiber count. Examining the brown adipose tissue, we found that the distance between each brown adipose tissue was noticeably reduced in the knockout mice. Lastly, in the pancreas, a significant reduction in the number of islets was observed in the knockout mice.
Furthermore, our investigation unveiled a significant downregulation of Bdnf mRNA expression levels in both skeletal muscle and pancreas in Rbm4 double knockout mice. This downregulation was accompanied by reduced expression levels of several key molecular markers. Surprisingly, the intraperitoneal injection of DHF, an agonist of TrkB, had the remarkable ability to fully restore Bdnf expression in RBM4 double knockout mice. These findings collectively underscore the critical role of RBM4 in the regulation of Bdnf and demonstrate the efficacy of DHF as a potential therapeutic intervention.
By expanding our understanding of the biological functions of RBM4 and its associated pathological mechanisms, our study paves the way for innovative pharmaceutical development strategies. These findings not only shed light on the molecular and cellular functions of RBM4 but also hold clinical relevance with the potential to impact future medical treatments.