The murine ortholog of notchless, a direct regulator of the notch pathway in Drosophila melanogaster, is essential for survival of inner cell mass cells.
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.
Cormier
Sarah
S
Unité Biologie du Développement, CNRS URA 2578, Institut Pasteur, Paris, France.
Le Bras
Stéphanie
S
Souilhol
Céline
C
Vandormael-Pournin
Sandrine
S
Durand
Béatrice
B
Babinet
Charles
C
Baldacci
Patricia
P
Cohen-Tannoudji
Michel
M
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D019070:Cell Lineage / Q000235:genetics*; D004331:Drosophila melanogaster / Q000235:genetics / Q000502:physiology; D010064:Embryo Implantation / Q000235:genetics*; D004622:Embryo, Mammalian / Q000166:cytology*; D004625:Embryo, Nonmammalian / Q000166:cytology; D005260:Female; D005804:Genes, Lethal; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D051880:Receptors, Notch / Q000502:physiology*; D014981:Xenopus
D008565:Membrane Proteins; D051880:Receptors, Notch; C510343:notchless protein, mouse