PTBP1 promotes hematopoietic stem cell maintenance and red blood cell development by ensuring sufficient availability of ribosomal constituents

Ribosomopathies constitute a range of disorders associated with defective protein synthesis mainly affecting hematopoietic stem cells (HSCs) and erythroid development. Here we demonstrate that deletion of Polypyrimidine Tract Binding Protein 1 (PTBP1) in the hematopoietic compartment led to the development of a ribosomopathy-like condition. Specifically, loss of PTBP1 was associated with decreases in HSC self-renewal, erythroid differentiation and protein synthesis. Consistent with its function as a splicing regulator, PTBP1 deficiency led to splicing defects in hundreds of genes, and we demonstrate that the up-regulation of a specific isoform of CDC42 could partly mimic the protein synthesis defect associated with loss of PTBP1. Furthermore, PTBP1 deficiency was associated with a marked defect in ribosome biogenesis and a selective reduction in the translation of mRNAs encoding ribosomal proteins. Collectively, this work identifies PTBP1 as a key integrator of ribosomal functions and highlights the broad functional repertoire of RNA binding proteins. Overall design: RNA-seq transcriptomic analysis of FACS sorted bone marrow progenitors; HSC (Lin-, Sca-1+, c-kit+, CD150+, CD48-) preMegEs and pre-CFU-Es from Ptbp1 fl/fl (wt) and Ptbp1 -/- (KO) mice. Three biological replicates per genotype and population were sequenced.