PUBLICATION

The Integrator subunits function in hematopoiesis by modulating Smad/BMP signaling

Authors
Tao, S., Cai, Y., and Sampath, K.
ID
ZDB-PUB-090720-1
Date
2009
Source
Development (Cambridge, England)   136(16): 2757-2765 (Journal)
Registered Authors
Sampath, Karuna, Tao, Shijie
Keywords
Hematopoiesis, Integrator proteins, RNA splicing, Smad/BMP signaling, Zebrafish
MeSH Terms
  • In Situ Hybridization
  • Cell Differentiation/physiology
  • Zebrafish/embryology*
  • Zebrafish/genetics
  • Multiprotein Complexes/metabolism
  • Bone Morphogenetic Proteins/genetics
  • Bone Morphogenetic Proteins/metabolism*
  • Gene Knockdown Techniques
  • Oligonucleotides, Antisense/genetics
  • Oligonucleotides, Antisense/metabolism
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
  • Smad Proteins/genetics
  • Smad Proteins/metabolism*
  • Erythrocytes/cytology
  • Erythrocytes/physiology
  • Protein Subunits/genetics
  • Protein Subunits/metabolism*
  • Animals
  • Signal Transduction/physiology*
  • Stem Cells/cytology
  • Stem Cells/physiology
  • Hematopoiesis/physiology*
  • RNA, Small Nuclear/genetics
  • RNA, Small Nuclear/metabolism
(all 25)
PubMed
19605500 Full text @ Development
Abstract
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.
Genes / Markers
Figures
Figure Gallery (15 images) / 2
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
WT + MO1-ints5 + MO2-ints5standard conditionsSphere
WT + MO1-ints5 + MO2-ints5standard conditions30%-epiboly
WT + MO1-ints5 + MO2-ints5standard conditionsPrim-5
WT + MO1-ints5 + MO2-ints5standard conditionsPrim-5
WT + MO1-ints5 + MO2-ints5standard conditionsPrim-5
WT + MO1-ints5 + MO2-ints5standard conditionsPrim-5
WT + MO1-ints5 + MO2-ints5standard conditionsPrim-5
WT + MO1-ints5 + MO2-ints5standard conditionsPrim-5
WT + MO1-ints5 + MO2-ints5standard conditionsPrim-5
WT + MO1-ints5 + MO2-ints5standard conditionsPrim-15
1 - 10 of 16
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Mutations / Transgenics
No data available
Human Disease / Model
No data available
Sequence Targeting Reagents
Target Reagent Reagent Type
ints5MO1-ints5MRPHLNO
ints5MO2-ints5MRPHLNO
ints9MO1-ints9MRPHLNO
ints11MO2-ints11MRPHLNO
ints11MO1-ints11MRPHLNO
1 - 5 of 5
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Fish
Fish
WT
WT + MO1-ints5 + MO2-ints5
WT + MO1-ints9
WT + MO2-ints11
1 - 4 of 4
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Antibodies
Name Type Antigen Genes Isotypes Host Organism
AB1-int5polyclonal
    		Rabbit
    Ab2-smadpolyclonal
      		Rabbit
      Ab2-tubbmonoclonal
        		IgG1Mouse
        1 - 3 of 3
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        Orthology
        No data available
        Engineered Foreign Genes
        No data available
        Mapping
        No data available
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        Citation
        Tao, S., Cai, Y., and Sampath, K. (2009) The Integrator subunits function in hematopoiesis by modulating Smad/BMP signaling. Development (Cambridge, England). 136(16):2757-2765.