Serine Hydroxymethyltransferase 2 Deficiency in the Hematopoietic System Disrupts Erythropoiesis and Induces Anemia in Murine Models

Serine and folate metabolism play critical roles in erythroid development in both embryonic and adult mice; however, the precise roles of these metabolic pathways in erythropoiesis and the pathophysiology of anemia remain inadequately characterized in the literature. To delineate the contributions of serine and folate metabolism to erythroid differentiation, we focused on serine hydroxymethyltransferase 2 (SHMT2), a key regulatory enzyme within these metabolic pathways. Using gene-editing techniques, we created fetal and adult mouse models with targeted deletion of in the hematopoietic system. Our findings demonstrated that the deletion of within the hematopoietic system led to the distinctive anemia phenotype in both fetal and adult mice. Detailed progression analysis of anemia revealed that deletion exerts stage-specific effects on the development and maturation of erythroid cells. Specifically, deficiency promoted erythroid differentiation in the R2 (CD71 Ter119) cell population residing in the bone marrow while concurrently inhibiting the proliferation and erythroid differentiation of the R3 (CD71 Ter119) cell population. This disruption resulted in developmental arrest at the R3 stage, significantly contributing to the anemia phenotype observed in the models. This study elucidates the critical role of in erythroid development within the hematopoietic system, highlighting the underlying mechanisms of erythroid developmental arrest associated with loss.