Developmental stage-specific changes in protein synthesis differentially sensitize hematopoietic stem cells and erythroid progenitors to impaired ribosome biogenesis

Abstract

Ribosomopathies encompass a collection of human genetic disorders that often arise from mutations in ribosomal proteins or ribosome biogenesis factors. Despite ubiquitous requirement of ribosomes for protein synthesis, ribosomopathies present with tissue- and cell-type-specific disorders, and blood is particularly affected. Several ribosomopathies present with congenital anemias and bone marrow failure, and accordingly, erythroid lineage cells and hematopoietic stem cells (HSCs) are preferentially impaired by ribosomal dysfunction. However, the factors that influence this cell-type-specific sensitivity are incompletely understood. Here, we show that protein synthesis rates change during HSC and erythroid progenitor ontogeny. Fetal HSCs exhibit significantly higher protein synthesis than adult HSCs. Despite protein synthesis differences, reconstituting activity of both fetal and adult HSCs is severely disrupted by a ribosomal mutation (Rpl24Bst/+). In contrast, fetal erythroid lineage progenitors exhibit significantly lower protein synthesis than their adult counterparts. Protein synthesis declines during erythroid differentiation, but the decline starts earlier in fetal differentiation than in adults. Strikingly, the Rpl24Bst/+ mutation impairs fetal, but not adult erythropoiesis, by impairing proliferation at fetal erythroid progenitor stages with the lowest protein synthesis relative to their adult counterparts. Thus, developmental and cell-type-specific changes in protein synthesis can sensitize hematopoietic cells to impaired ribosome biogenesis. Key PointsO_LIFetal HSCs synthesize much more protein per hour than young adult HSCs in vivo C_LIO_LIFetal erythroid progenitors synthesize much less protein per hour than young adult erythroid progenitors in vivo C_LIO_LIDifferences in protein synthesis dynamics distinguish fetal and adult erythroid differentiation C_LIO_LIA ribosomal mutation that reduces protein synthesis impairs fetal and adult HSCs C_LIO_LIReduced protein synthesis impairs fetal but not adult erythroid progenitors C_LI