The Integrator subunits function in hematopoiesis by modulating Smad/BMP signaling
2009
Hematopoiesis, the dynamic process of blood cell development, is regulated
by the activity of the bone morphogenetic protein (BMP) signaling pathway and
by many transcription factors. However, the molecules and mechanisms that
regulate BMP/Smad signaling in hematopoiesis are largely unknown. Here, we
show that the Integrator complex, an evolutionarily conserved group of
proteins, functions in zebrafish hematopoiesis by modulating Smad/BMP
signaling. The Integrator complex proteins are known to directly interact with
RNA polymerase II to mediate 3′ end processing of U1 and U2 snRNAs. We
have identified several subunits of the Integrator complex in zebrafish.
Antisense morpholino-mediated knockdown of the Integrator subunit 5 (Ints5) in
zebrafish embryos affects U1 and U2 snRNA processing, leading to aberrant
splicing of smad1 and smad5 RNA, and reduced expression of
the hematopoietic genes stem cell leukemia ( scl , also known
as tal1 ) and gata1 . Blood smears from ints5
morphant embryos show arrested red blood cell differentiation, similar to
scl -deficient embryos. Interestingly, targeting other Integrator
subunits also leads to defects in smad5 RNA splicing and arrested
hematopoiesis, suggesting that the Ints proteins function as a complex to
regulate the BMP 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 regulates the switch from
primitive hematopoietic stem cell identity and blood cell differentiation by
modulating Smad function.
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