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Molecular and Cellular Biology, May 2006, p. 3541-3549, Vol. 26, No. 9
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.9.3541-3549.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

The Murine Ortholog of Notchless, a Direct Regulator of the Notch Pathway in Drosophila melanogaster, Is Essential for Survival of Inner Cell Mass Cells

Sarah Cormier,^1, Stéphanie Le Bras,^1,, Céline Souilhol,¹ Sandrine Vandormael-Pournin,¹ Béatrice Durand,² Charles Babinet,^1* Patricia Baldacci,^1, and Michel Cohen-Tannoudji¹

Unité Biologie du Développement, CNRS URA 2578, Institut Pasteur, Paris, France,¹ Unité des Rétrovirus et Transfert Génétiques, Institut Pasteur, Paris, France²

Received 20 December 2005/ Accepted 28 January 2006

Notch signaling is an evolutionarily conserved pathway involved in intercellular communication and is essential for proper cell fate choices. Numerous genes participate in the modulation of the Notch signaling pathway activity. Among them, Notchless (Nle) is a direct regulator of the Notch activity identified in Drosophila melanogaster. Here, we characterized the murine ortholog of Nle and demonstrated that it has conserved the ability to modulate Notch signaling. We also generated mice deficient for mouse Nle (mNle) and showed that its disruption resulted in embryonic lethality shortly after implantation. In late mNle^–/– blastocysts, inner cell mass (ICM) cells died through a caspase 3-dependent apoptotic process. Most deficient embryos exhibited a delay in the temporal down-regulation of Oct4 expression in the trophectoderm (TE). However, mNle-deficient TE was able to induce decidual swelling in vivo and properly differentiated in vitro. Hence, our results indicate that mNle is mainly required in ICM cells, being instrumental for their survival, and raise the possibility that the death of mNle-deficient embryos might result from abnormal Notch signaling during the first steps of development.

S.C. and S.L.B. contributed equally to this work.

Present address: Department of Biology, Johns Hopkins University, Baltimore, Md.

Present address: Unité Biologie et Génétique du Paludisme, Institut Pasteur, Paris, France.

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