Reciprocal activation of GATA-1 and PU.1 marks initial specification of hematopoietic stem cells into myeloerythroid and myelolymphoid lineages.
A hierarchical hematopoietic development with myeloid versus lymphoid bifurcation has been proposed downstream of the multipotent progenitor (MPP) stage, based on prospective isolation of progenitors capable of generating only myeloerythroid cells (common myeloid progenitor, CMP) or only lymphocytes (common lymphoid progenitor, CLP). By utilizing GATA-1 and PU.1 transcription factor reporters, here we identified progenitor populations that are precursors for either CMPs or CLPs. Two independent populations expressing either GATA-1 or PU.1 resided within the CD34(+)Sca-1(+)c-Kit(+) MPP fraction. The GATA-1(+) MPP displayed potent myeloerythroid potential without giving rise to lymphocytes, whereas the PU.1(+) MPP showed granulocyte/monocyte/lymphoid-restricted progenitor activity without megakaryocyte/erythroid differentiation. Furthermore, GATA-1(+) and PU.1(+) MPPs possessed huge expansion potential and differentiated into the original CMPs and CLPs, respectively. Thus, the reciprocal activation of GATA-1 and PU.1 primarily organizes the hematopoietic lineage fate decision to form the earliest hematopoietic branchpoint that comprises isolatable myeloerythroid and myelolymphoid progenitor populations.
Arinobu
Yojiro
Y
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Mizuno
Shin-ichi
S
Chong
Yong
Y
Shigematsu
Hirokazu
H
Iino
Tadafumi
T
Iwasaki
Hiromi
H
Graf
Thomas
T
Mayfield
Robin
R
Chan
Susan
S
Kastner
Philippe
P
Akashi
Koichi
K
D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D000067696:Ataxin-1; D000067528:Ataxins; D002454:Cell Differentiation; D019070:Cell Lineage; D015672:Erythroid Precursor Cells / Q000166:cytology*; D050982:GATA1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D017930:Genes, Reporter; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D008214:Lymphocytes / Q000166:cytology; D054503:Lymphoid Progenitor Cells / Q000166:cytology*; D008533:Megakaryocytes / Q000166:cytology; D051379:Mice; D008954:Models, Biological; D039902:Multipotent Stem Cells / Q000166:cytology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics*; D000099232:Proto-Oncogene Protein Spi-1
D018952:Antigens, CD34; D000067696:Ataxin-1; D000067528:Ataxins; D050982:GATA1 Transcription Factor; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C000593750:Atxn1 protein, mouse