Common tissue-specific expressions and regulatory mechanisms of c-KIT isoforms with and without GNNK and GNSK sequences across five mammals

c-KIT is a transmembrane receptor tyrosine kinase involved in various signaling pathways. Alternative pre-mRNA splicing of KIT results in isoforms that differ in the presence or absence of four amino acid sequences in the extracellular juxtamembrane region, such as, isoforms with and without the GNNK sequence (GNNK+ and GNNK-, respectively) in humans and mice, and those with and without GNSK (GNSK+ and GNSK-, respectively) in domestic dogs, cats, and sheep. These isoforms have been extensively studied as disease-associated splice variants with differing kinase activities. However, the expression patterns and regulatory mechanisms of each isoform in various animal species remain poorly understood. In the present study, a comprehensive expression analysis was conducted using tissue-wide transcriptome data from humans, mice, domestic dogs, domestic cats, and domestic sheep. We found that the expression ratio of c-KIT isoforms differs across tissues, and such features are conserved across animal species: GNNK+ and GNSK+ isoforms have high expression ratios in the central nervous system, while GNNK- and GNSK- predominate in other tissues. Furthermore, the RNA-binding proteins NOVA1/2 were involved in regulating such tissue-specific isoform expressions through alternative 5' splice donor site selections.