title: Lineage-instructive function of C/EBPα in multipotent hematopoietic cells and early thymic progenitors.
abstract: Hematopoiesis is tightly controlled by transcription regulatory networks, but how and when specific transcription factors control lineage commitment are still largely unknown. Within the hematopoietic stem cell (Lin(-)Sca-1(+)c-Kit(+)) compartment these lineage-specific transcription factors are expressed at low levels but are up-regulated with the process of lineage specification. CCAAT/enhancer binding protein α (C/EBPα) represents one of these factors and is involved in myeloid development and indispensable for formation of granulocytes. To track the cellular fate of stem and progenitor cells, which express C/EBPα, we developed a mouse model expressing Cre recombinase from the Cebpa promoter and a conditional EYFP allele. We show that Cebpa/EYFP(+) cells represent a significant subset of multipotent hematopoietic progenitors, which predominantly give rise to myeloid cells in steady-state hematopoiesis. C/EBPα induced a strong myeloid gene expression signature and down-regulated E2A-induced regulators of early lymphoid development. In addition, Cebpa/EYFP(+) cells compose a fraction of early thymic progenitors with robust myeloid potential. However, Cebpa/EYFP(+) multipotent hematopoietic progenitors and early thymic progenitors retained the ability to develop into erythroid and T-lymphoid lineages, respectively. These findings support an instructive but argue against a lineage-restrictive role of C/EBPα in multipotent hematopoietic and thymic progenitors.
authors.affiliation: Department of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Wölfler
authors.forename: Astrid A
authors.initials: AA
authors.lastname: Danen-van Oorschot
authors.forename: Jurgen R
authors.initials: JR
authors.lastname: Haanstra
authors.forename: Marijke
authors.initials: M
authors.lastname: Valkhof
authors.forename: Claudia
authors.initials: C
authors.lastname: Bodner
authors.forename: Eric
authors.initials: E
authors.lastname: Vroegindeweij
authors.forename: Paulette
authors.initials: P
authors.lastname: van Strien
authors.forename: Alexandra
authors.initials: A
authors.lastname: Novak
authors.forename: Tom
authors.initials: T
authors.lastname: Cupedo
authors.forename: Ivo P
authors.initials: IP
authors.lastname: Touw
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism*; D002451:Cell Compartmentation; D019070:Cell Lineage; D049109:Cell Proliferation; D003114:Colony-Forming Units Assay; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism; D009924:Organ Culture Techniques; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013950:Thymus Gland / Q000166:cytology* / Q000196:embryology / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D022763:CCAAT-Enhancer-Binding Protein-alpha; D008164:Luminescent Proteins; D012333:RNA, Messenger; C054562:yellow fluorescent protein, Bacteria; C045073:Cre recombinase; D019426:Integrases