Our work on temperature-controlled alternative splicing and gene expression started when we found that alternative splicing of U2AF26 is controlled in a time-of-the-day dependent manner and that this splicing event plays a role in resetting the circadian clock in vivo. This is the first functionally well-characterized rhythmic alternative splicing event in a mammalian system (Preussner et al., Mol Cell, 2014). We then set out to determine cis-acting elements and trans-acting factors that control rhythmic alternative splicing. We found that circadian changes in body temperature act as systemic signal to globally control alternative splicing and gene expression through regulating the phosphorylation status of SR proteins (Preussner et al., Mol Cell, 2017). Next we showed that the activity of a family of kinases, CLKs, is extremely temperature-sensitive in a narrow temperature range due to conformational changes in the active center and that this leads to reduced kinase activity at the upper end of the physiologically relevant temperature in diverse organisms, suggesting, amongst many other functional consequences, a connection to temperature-dependent sex determination in reptiles (Haltenhof et al., Mol Cell, 2020). Altered CLK activity then translates into global changes in alternative splicing through regulating the phosphorylation status of SR proteins. Interestingly, we have also shown that many temperature-controlled alternative splicing events control poison exons that induce nonsense-mediated decay (AS-NMD), thus providing a means how temperature-controlled alternative splicing can also control gene expression. In fact, AS-NMD plays a substantial role in controlling the temperature-dependent transcriptome (Neumann et al., Embo Rep, 2020), which has diverse functional consequences, some of which we are currently analyzing. For example, we have recently shown that subtle changes in body temperature alter STAT2 levels through AS-NMD, thereby controlling the antiviral defense. This finding may contribute to explain why older individuals with lower body temperature are more susceptible to severe Sars-CoV-2 infection than children (Los et al., NAR, 2022). With this work, we have characterized the full cascade, from a body temperature sensor to altered phosphorylation of SR proteins, a global change in alternative splicing and gene expression through AS-NMD and a clinically relevant functional consequence. Finally, we have discovered the long-elusive mechanism that controls cold-induced expression of the neuro- and cytoprotective protein RBM3. This solely depends on AS-NMD, which leads to degradation of the RBM3 mRNA at warmer temperature (already at 37°C). We have developed ASOs that target the poison exon of RBM3 to inhibit NMD and induce its expression at normothermia. These ASOs are highly neuroprotective in a mouse model for prion disease and hold immense potential to be developed for use in humans in diverse conditions from neonatal hypoxic ischemic encephalopathy to Alzheimer’s disease (Preussner et al., Embo Mol Med, 2023).