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Notch signalling regulates stem cell numbers in vitro and in vivo


The hope of developing new transplantation therapies for degenerative diseases is limited by inefficient stem cell growth and immunological incompatibility with the host1,2. Here we show that Notch receptor activation induces the expression of the specific target genes hairy and enhancer of split 3 (Hes3) and Sonic hedgehog (Shh) through rapid activation of cytoplasmic signals, including the serine/threonine kinase Akt, the transcription factor STAT3 and mammalian target of rapamycin, and thereby promotes the survival of neural stem cells. In both murine somatic and human embryonic stem cells, these positive signals are opposed by a control mechanism that involves the p38 mitogen-activated protein kinase. Transient administration of Notch ligands to the brain of adult rats increases the numbers of newly generated precursor cells and improves motor skills after ischaemic injury. These data indicate that stem cell expansion in vitro and in vivo, two central goals of regenerative medicine, may be achieved by Notch ligands through a pathway that is fundamental to development and cancer3,4,5.

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Figure 1: Notch ligands activate second messenger signalling and support NSC (E13.5) survival in vitro.
Figure 2: Mediators and modulators of Notch signalling in NSC (E13.5) cultures.
Figure 3: A stem cell signalling pathway that affects survival and differentiation.
Figure 4: In vitro and in vivo data support a general role for the signalling model in stem cell biology.

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We thank R. Kageyama and T. Kitamura for the Hes3 and STAT3 plasmids. This research was supported in part by the Intramural Research Program of the NIH, NINDS.

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Correspondence to Ronald D. G. McKay.

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Reprints and permissions information is available at The authors declare no competing financial interests.

Supplementary information

Supplementary Figure 1

A schematic representation of this work. (PDF 154 kb)

Supplementary Figure 2

Notch ligands activate second messenger signalling and support NSC (E13.5) survival in vitro. (PDF 104 kb)

Supplementary Figure 3

Notch activation promotes the generation of adult NSC in vivo. (PDF 127 kb)

Supplementary Figure

This file contains the Supplementary Figure Legends and Supplementary Tables 1–3. (DOC 67 kb)

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Androutsellis-Theotokis, A., Leker, R., Soldner, F. et al. Notch signalling regulates stem cell numbers in vitro and in vivo. Nature 442, 823–826 (2006).

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