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First published online January 10, 2007
doi: 10.1242/10.1242/dev.02733

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Mapping the consequence of Notch1 proteolysis in vivo with NIP-CRE

Marc Vooijs^1,2,*,, Chin-Tong Ong¹, Brandon Hadland¹, Stacey Huppert^1,, Zhenyi Liu¹, Jeroen Korving², Maaike van den Born², Thaddeus Stappenbeck³, Yumei Wu¹, Hans Clevers² and Raphael Kopan^1,

¹ Department of Molecular Biology and Pharmacology and the Department of Medicine, Division of Dermatology, Washington University Medical School, St Louis, MO 63110, USA.
² Netherlands Institute for Developmental Biology, Hubrecht Laboratory, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands.
³ Department of Pathology & Immunology, Washington University School of Medicine, St Louis, MO 63110, USA.

Authors for correspondence (e-mail: m.vooijs{at}umcutrecht.nl; kopan{at}wustl.edu)

Accepted 8 November 2006

The four highly conserved Notch receptors receive short-range signals that control many biological processes during development and in adult vertebrate tissues. The involvement of Notch1 signaling in tissue self-renewal is less clear, however. We developed a novel genetic approach N₁IP-CRE (Notch1 Intramembrane Proteolysis) to follow, at high resolution, the descendents of cells experiencing Notch1 activation in the mouse. By combining N₁IP-CRE with loss-of-function analysis, Notch activation patterns were correlated with function during development, self-renewal and malignancy in selected tissues. Identification of many known functions of Notch1 throughout development validated the utility of this approach. Importantly, novel roles for Notch1 signaling were identified in heart, vasculature, retina and in the stem cell compartments of self-renewing epithelia. We find that the probability of Notch1 activation in different tissues does not always indicate a requirement for this receptor and that gradients of Notch1 activation are evident within one organ. These findings highlight an underappreciated layer of complexity of Notch signaling in vivo. Moreover, NIP-CRE represents a general strategy applicable for monitoring proteolysis-dependent signaling in vivo.

Key words: Notch, Regulated intramembrane proteolysis (RIP), Cre recombinase, Fate mapping, Stem cells, Mouse

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