Nature Immunology6, 314 - 322 (2005)
Published online: 23 January 2005; | doi:10.1038/ni1164
Integration of Notch and Wnt signaling in hematopoietic stem cell maintenance
Andrew W Duncan1, 3, Frédérique M Rattis1, 3, Leah N DiMascio1, Kendra L Congdon1, Gregory Pazianos1, Chen Zhao1, Keejung Yoon2, J Michael Cook1, Karl Willert1, Nicholas Gaiano2
& Tannishtha Reya1
1
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
2
Department of Neurology and Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
3
These authors contributed equally to this work.
Correspondence should be addressed to Tannishtha Reya t.reya@duke.edu
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.
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