Integration of Notch and Wnt signaling in hematopoietic stem cell maintenance.
A fundamental question in hematopoietic stem cell (HSC) biology is how self-renewal is controlled. Here we show that the molecular regulation of two critical elements of self-renewal, inhibition of differentiation and induction of proliferation, can be uncoupled, and we identify Notch signaling as a key factor in inhibiting differentiation. Using transgenic Notch reporter mice, we found that Notch signaling was active in HSCs in vivo and downregulated as HSCs differentiated. Inhibition of Notch signaling led to accelerated differentiation of HSCs in vitro and depletion of HSCs in vivo. Finally, intact Notch signaling was required for Wnt-mediated maintenance of undifferentiated HSCs but not for survival or entry into the cell cycle in vitro. These data suggest that Notch signaling has a dominant function in inhibiting differentiation and provide a model for how HSCs may integrate multiple signals to maintain the stem cell state.
Duncan
Andrew W
AW
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Rattis
Frédérique M
FM
DiMascio
Leah N
LN
Congdon
Kendra L
KL
Pazianos
Gregory
G
Zhao
Chen
C
Yoon
Keejung
K
Cook
J Michael
JM
Willert
Karl
K
Gaiano
Nicholas
N
Reya
Tannishtha
T
D000818:Animals; D049109:Cell Proliferation; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D051880:Receptors, Notch; D015398:Signal Transduction; D051153:Wnt Proteins
D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051880:Receptors, Notch; D051153:Wnt Proteins