RNA-Binding Proteins PCBP1 and PCBP2 Are Critical Determinants of Murine Erythropoiesis

Abstract

We have previously demonstrated that the two paralogous RNA binding protein, PCBP1 and PCBP2, are individually essential for mouse development: Pcbp1-null embryos are peri-implantation lethal while Pcbp2-null embryos lose viability at mid-gestation. Mid-gestation Pcbp2−/− embryos revealed a complex phenotype that included loss of certain hematopoietic determinants. Whether PCBP2 directly contributes to erythropoietic differentiation and whether PCBP1 has a role in this process remained undetermined. Here we selectively inactivate the genes encoding these two RNA-binding proteins during differentiation of the erythroid lineage in the developing mouse embryo. Individual inactivation of either locus fails to impact viability or blood formation. However, combined inactivation of the two loci results in mid-gestational repression of erythroid/hematopoietic gene expression, loss of blood formation, and fetal demise. Orthogonal ex-vivo analyses of primary erythroid progenitors selectively depleted of these two RNA binding proteins revealed that they mediate a combination of overlapping and isoform-specific impacts on hematopoietic lineage transcriptome, impacting both mRNA representation and exon splicing. These data lead us to conclude that PCBP1 and PCBP2 mediate functions critical to differentiation of the erythroid lineage.