<i>Rbfox2</i> selectively governs hematopoietic stem cell self-renewal by regulating proteostasis

Self-renewing hematopoietic stem cells (HSCs) generate all blood cells and give rise to long-term reconstitution of the hematopoietic system after transplantation, but the molecular mechanisms that specifically regulate HSCs remain poorly defined. Here, we found that HSCs displayed a distinct messenger RNA alternative splicing pattern and preferentially expressed <i>Rbfox2</i>, an alternative splicing regulator, compared with multipotent progenitors (MPPs). Deletion of <i>Rbfox2</i> from the hematopoietic compartment specifically depleted HSCs, but not progenitors in the adult bone marrow. <i>Rbfox1</i> did not function redundantly with <i>Rbfox2</i> in HSCs. Mechanistically, <i>Rbfox2</i> loss led to proteostasis stress, including increased protein synthesis rate and accumulated misfolded/unfolded protein contents, in HSCs, but not in progenitors. Small molecules that restore proteostasis rescued HSC defects in <i>Rbfox2</i>-deficient mice. Our work thus reveals that HSCs, but not progenitors, selectively rely on <i>Rbfox2</i> for their self-renewal and maintenance.