Upf2, also known as UP-Frameshift 2, is a key component of the nonsense-mediated mRNA decay (NMD) pathway. NMD is a conserved co-translational mRNA surveillance and turnover pathway across eukaryotes, which degrades defective mRNAs and regulates the stability of a significant portion of the transcriptome [3]. Upf2 has been shown to play important roles in various biological processes, and its study in genetic models has provided valuable insights into its functions.

In pancreatic inflammatory myofibroblastic tumors, an alternative spliced UPF2 mRNA was found, resulting in a truncated UPF2 protein that disrupted the NMD pathway, upregulated NMD targets like cdkn1a, and might contribute to tumorigenesis [1]. In mice, neuron-specific disruption of UPF2 in adulthood led to attenuated learning, memory, and synaptic plasticity, as it regulated Glutamate Receptor 1 surface levels in dendrites [2]. Inhibition of Upf2-dependent NMD in mice caused behavioral and neurophysiological abnormalities due to activated immune response, and anti-inflammatory drugs could reverse these deficits [4]. Deletion of Upf2 in mouse embryonic neural progenitor cells led to perinatal microcephaly, prolonging the cell cycle of radial glia progenitor cells and reducing upper-layer neurons [5]. Loss of UPF2 in gastric cancer cells caused resistance to ATR inhibitors, altering cell-cycle progression and DNA damage responses [6].

In conclusion, Upf2 is crucial for the NMD pathway. Its disruption in KO/CKO mouse models has revealed its roles in diseases such as pancreatic tumors, neurodevelopmental disorders, and gastric cancer. These studies enhance our understanding of the biological functions of Upf2 and its significance in disease mechanisms, potentially guiding the development of new therapeutic strategies.