Unconventional Control of Fetal Hematopoiesis by Ribosomal Subunits RPS19 and RPL5

Ribosomopathies are associated with anemia; yet, the precise control of ribosomal protein (RP) stoichiometry and activity during erythroid development remains elusive. Using Diamond-Blackfan anemia (DBA) as a model, we generated novel in vivo models of RP haploinsufficiency to define the roles of small and large RP subunits in fetal hematopoiesis. Rpl5 haploinsufficiency caused prenatal lethality due to a reduction in erythroid translation. Conversely, Rps19 haploinsufficiency led to neonatal stem cell exhaustion and impaired erythroid progenitor expansion, resulting from combined translational and transcriptional defects. The stem cell factor RUNX1 is upregulated in RPS19-haploinsufficient DBA patients and its deletion partially rescued hematopoiesis in Rps19 mutant mice. Our findings reveal distinct, subunit-specific roles for RPs in fetal hematopoiesis and demonstrate that imbalanced RP stoichiometry disrupts developmental programs, providing key insights into DBA pathogenesis and patient heterogeneity while underscoring the importance of balanced RP expression in stem cell and erythroid progenitor development.