Haploinsufficiency of GATA-2 perturbs adult hematopoietic stem-cell homeostasis.
The zinc finger transcription factor GATA-2 plays a fundamental role in generating hematopoietic stem-cells in mammalian development. Less well defined is whether GATA-2 participates in adult stem-cell regulation, an issue we addressed using GATA-2 heterozygote mice that express reduced levels of GATA-2 in hematopoietic cells. While GATA-2+/- mice demonstrated decreases in some colony-forming progenitors, the most prominent changes were observed within the stem-cell compartment. Heterozygote bone marrow had a lower abundance of Lin(-)c-kit(+)Sca-1(+)CD34- cells and performed poorly in competitive transplantation and quantitative week-5 cobblestone area-forming cell (CAFC) assays. Furthermore, a stem-cell-enriched population from GATA1+/- marrow was more quiescent and exhibited a greater frequency of apoptotic cells associated with decreased expression of the anti-apoptotic gene Bcl-xL. Yet the self-renewal potential of the +/- stem-cell compartment, as judged by serial transplantations, was unchanged. These data indicate compromised primitive cell proliferation and survival in the setting of a lower GATA-2 gene dose without a change in the differentiation or self-renewal capacity of the stem-cells that remain. Thus, GATA-2 dose regulates adult stem-cell homeostasis by affecting select aspects of stem cell function.
Rodrigues
Neil P
NP
Center for Regenerative Medicine and Technology, Massachusetts General Hospital, Boston, MA 02129, USA.
Janzen
Viktor
V
Forkert
Randolf
R
Dombkowski
David M
DM
Boyd
Ashleigh S
AS
Orkin
Stuart H
SH
Enver
Tariq
T
Vyas
Paresh
P
Scadden
David T
DT
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics*; D005260:Female; D050989:GATA2 Transcription Factor; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006579:Heterozygote; D006706:Homeostasis; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics*
D004268:DNA-Binding Proteins; D050989:GATA2 Transcription Factor; C494712:Gata2 protein, mouse; D012333:RNA, Messenger; D014157:Transcription Factors