Kit structural mutations associated with the porcine dominant white phenotype impair hematopoiesis in mice

Kit encodes a receptor tyrosine kinase crucial for various biological processes. To investigate how Kit structural mutations associated with the porcine dominant white phenotype affect hematopoiesis, we utilized three distinct gene-edited mouse models: Kit coding sequence (CDS) duplication (Kitdup/+), Kit exon 17 deletion (KitD17/+), and a compound heterozygous model carrying both mutations (Kitdup/D17), along with wild-type controls (Kit+/+). We observed that the Kit structural mutations significantly impaired erythropoiesis in bone marrow, resulting in hypoplastic macrocytic anemia and compensatory erythropoiesis in the spleen. Transcriptomic analyses revealed that these structural Kit mutations attenuate PI3K and MAPK signaling activation and downregulate genes essential for erythroid differentiation. Our findings provide novel mechanistic insights into how Kit mutations contribute to hematopoietic dysfunction.