title: The transcription factor Mxd4 controls the proliferation of the first blood precursors at the onset of hematopoietic development in vitro.
abstract: OBJECTIVE
  The balance between proliferation and differentiation during hematopoietic development in the embryo is a complex process, the detailed molecular mechanisms of which remain to be fully characterized. The transcription factor Mxd4, a member of the Myc-Max-Mad network, was identified in a global gene expression profiling screen as being tightly regulated at the onset of hematopoietic lineage specification upon in vitro differentiation of mouse embryonic stem cells. Our study investigated the Mxd4 expression pattern at the onset of hematopoiesis and the biological relevance of its sharp and transient downregulation.
  
  
  METHODS
  To study the expression pattern and role of Mxd4 at the onset of hematopoiesis, the in vitro differentiation of embryonic stem cells was used as a model system. Gain of function assays were performed using a doxycycline-inducible embryonic stem cell system.
  
  
  RESULTS
  We show here that Mxd4 expression is transiently downregulated at an early stage of commitment to the hematopoietic lineage. Enforced expression of Mxd4 at this period of differentiation results in a defect in hematopoietic progenitor development, with impaired development of both primitive and definitive blood lineages. This effect is due to a severe decrease in cell proliferation, with an increased frequency of cells in the G(0)/G(1) phase of the cell cycle, alongside a reduced frequency of cells in the S phase.
  
  
  CONCLUSIONS
  Together our results indicate that during embryonic hematopoietic differentiation Mxd4 is an important player in the regulation of blood progenitor proliferation, and suggest that downregulation of its expression might be required for a proliferative burst preceding lineage specification.
authors.affiliation: Cancer Research UK Stem Cell Hematopoiesis Group, Paterson Institute for Cancer Research, University of Manchester, UK.
authors.forename: Katalin
authors.initials: K
authors.lastname: Boros
authors.forename: Georges
authors.initials: G
authors.lastname: Lacaud
authors.forename: Valerie
authors.initials: V
authors.lastname: Kouskoff
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000502:physiology*; D019070:Cell Lineage; D049109:Cell Proliferation; D005786:Gene Expression Regulation / Q000502:physiology; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006413:Hematopoietic System / Q000254:growth & development*; D051379:Mice; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C484347:MXD4 protein, human