Differential requirements for the activation domain and FOG-interaction surface of GATA-1 in megakaryocyte gene expression and development

Blood. 2005 Aug 15;106(4):1223-31. doi: 10.1182/blood-2005-02-0551. Epub 2005 Apr 28.


GATA1 is mutated in patients with 2 different disorders. First, individuals with a GATA1 mutation that blocks the interaction between GATA-1 and its cofactor Friend of GATA-1 (FOG-1) suffer from dyserythropoietic anemia and thrombocytopenia. Second, children with Down syndrome who develop acute megakaryoblastic leukemia harbor mutations in GATA1 that lead to the exclusive expression of a shorter isoform named GATA-1s. To determine the effect of these patient-specific mutations on GATA-1 function, we first compared the gene expression profile between wild-type and GATA-1-deficient megakaryocytes. Next, we introduced either GATA-1s or a FOG-binding mutant (V205G) into GATA-1-deficient megakaryocytes and assessed the effect on differentiation and gene expression. Whereas GATA-1-deficient megakaryocytes failed to undergo terminal differentiation and proliferated excessively in vitro, GATA-1s-expressing cells displayed proplatelet formation and other features of terminal maturation, but continued to proliferate aberrantly. In contrast, megakaryocytes that expressed V205G GATA-1 exhibited reduced proliferation, but failed to undergo maturation. Examination of the expression of megakaryocyte-specific genes in the various rescued cells correlated with the observed phenotypic differences. These studies show that GATA-1 is required for both normal regulation of proliferation and terminal maturation of megakaryocytes, and further, that these functions can be uncoupled by mutations in GATA1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Anemia, Dyserythropoietic, Congenital / genetics
  • Animals
  • Binding Sites
  • Carrier Proteins / metabolism
  • Cell Differentiation / genetics
  • Cell Proliferation
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / physiology*
  • Down Syndrome / genetics
  • Erythroid-Specific DNA-Binding Factors
  • GATA1 Transcription Factor
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Megakaryocytes / cytology*
  • Megakaryocytes / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Nuclear Proteins / metabolism
  • Thrombocytopenia / genetics
  • Transcription Factors / chemistry
  • Transcription Factors / genetics*
  • Transcription Factors / physiology*


  • Carrier Proteins
  • DNA-Binding Proteins
  • Erythroid-Specific DNA-Binding Factors
  • GATA1 Transcription Factor
  • Gata1 protein, mouse
  • Nuclear Proteins
  • Transcription Factors
  • Zfpm1 protein, mouse