The integrator subunits function in hematopoiesis by modulating SMAD/BMP signaling

Abstract

The Integrator complex proteins are known to directly interact with RNA polymerase II to mediate 3b end processing of U1 and U2 snRNAs. We have identified several subunits of the Integrator complex in zebrafish. Knock-down of the Integrator subunit 5 (Ints5) in zebrafish embryos causes aberrant splicing of smad1 and smad5 RNA, and reduced expression of the hematopoietic genes. Blood smears from ints5 morphant embryos show arrested red blood cell differentiation. Interestingly, targeting other Integrator subunits also leads to defects in smad5 RNA splicing and arrested hematopoiesis, suggesting that the Int proteins function as a complex to regulate the BMP (Bone Morphogenetic Protein) pathway during hematopoiesis. Our work establishes a link between the RNA processing machinery and the downstream effectors of BMP signaling, and reveals a new group of proteins that regulate the switch from primitive hematopoietic stem cell identity and blood cell differentiation by modulating Smad function.