Hematopoietic stem cell fate is established by the Notch-Runx pathway.
Identifying the molecular pathways regulating hematopoietic stem cell (HSC) specification, self-renewal, and expansion remains a fundamental goal of both basic and clinical biology. Here, we analyzed the effects of Notch signaling on HSC number during zebrafish development and adulthood, defining a critical pathway for stem cell specification. The Notch signaling mutant mind bomb displays normal embryonic hematopoiesis but fails to specify adult HSCs. Surprisingly, transient Notch activation during embryogenesis via an inducible transgenic system led to a Runx1-dependent expansion of HSCs in the aorta-gonad-mesonephros (AGM) region. In irradiated adults, Notch activity induced runx1 gene expression and increased multilineage hematopoietic precursor cells approximately threefold in the marrow. This increase was followed by the accelerated recovery of all the mature blood cell lineages. These data define the Notch-Runx pathway as critical for the developmental specification of HSC fate and the subsequent homeostasis of HSC number, thus providing a mechanism for amplifying stem cells in vivo.
Burns
Caroline Erter
CE
Stem Cell Program and Division of Hematology/Oncology Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Traver
David
D
Mayhall
Elizabeth
E
Shepard
Jennifer L
JL
Zon
Leonard I
LI
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000502:physiology; D001773:Blood Cells / Q000166:cytology / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage / Q000502:physiology* / Q000528:radiation effects; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism*; D047108:Embryonic Development / Q000502:physiology / Q000528:radiation effects; D005720:Gamma Rays; D018507:Gene Expression Regulation, Developmental / Q000502:physiology / Q000528:radiation effects; D006066:Gonads / Q000166:cytology / Q000502:physiology; D006410:Hematopoiesis / Q000502:physiology* / Q000528:radiation effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology / Q000528:radiation effects; D008650:Mesonephros / Q000166:cytology / Q000502:physiology; D009154:Mutation; D014916:Whole-Body Irradiation / Q000379:methods; D015027:Zebrafish / Q000033:anatomy & histology / Q000196:embryology* / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
D050676:Core Binding Factor Alpha 2 Subunit; D029961:Zebrafish Proteins; C472526:runx1 protein, zebrafish