RBP-Jκ-Dependent Notch Signaling Is Dispensable for Mouse Early Embryonic Development

Abstract

The Notch signaling pathway is an evolutionarily conserved signaling system which has been shown to be essential in cell fate specification and in numerous aspects of embryonic development in all metazoans thus far studied. We recently demonstrated that several components of the Notch signaling pathway, including the four Notch receptors and their five ligands known in mammals, are expressed in mouse oocytes, in mouse preimplantation embryos, or both. This suggested a possible implication of the Notch pathway in the first cell fate specification of the dividing mouse embryo, which results in the formation of the blastocyst. To address this issue directly, we generated zygotes in which both the maternal and the zygotic expression of Rbpsuh, a key element of the core Notch signaling pathway, were abrogated. We find that such zygotes give rise to blastocysts which implant and develop normally. Nevertheless, after gastrulation, these embryos die around midgestation, similarly to Rbpsuh-null mutants. This demonstrates that the RBP-J-dependent pathway, otherwise called the canonical Notch pathway, is dispensable for blastocyst morphogenesis and the establishment of the three germ layers, ectoderm, endoderm, and mesoderm. These results are discussed in the light of recent observations which have challenged this conclusion.

NOTCH activation interferes with cell fate specification in the gastrulating mouse embryo

“…These observations are consistent with a recent report demonstrating that whereas forced activation of NOTCH signalling in pre-implantation embryos can influence the segregation of the trophectoderm lineage, it does not prevent the formation of morphologically normal blastocysts at E3.5 (Rayon et al, 2014). Together with previous reports showing normal development up to E8.0 of embryos lacking maternal and zygotic expression of key components of the NOTCH pathway (Shi and Stanley, 2006;Souilhol et al, 2006), our results demonstrate that the NOTCH signalling pathway is not a crucial regulator of mouse embryonic development before gastrulation.…”

“…Genotyping of mice was performed using conditions described in Souilhol et al (2006) for the Cre lines and Rbpj flox and Rbpj Δ alleles, and in Soriano (1999) for Rosa26 N1ICD allele. Mice were maintained under a 12-h light cycle and embryos of different genotypes were obtained from natural matings.…”

“…Nevertheless, they are indistinguishable from wild-type embryos at E8.0, by which stage all three germ layers have formed (reviewed by Yoon and Gaiano, 2005). Moreover, mutant embryos lacking maternal and zygotic RBPJ or O-fucosyltransferase 1 (POFUT1), both essential components of the canonical NOTCH signalling pathway, develop normally until E8.0 (Shi and Stanley, 2006;Souilhol et al, 2006).…”

Endocrine Pancreas Development and Regeneration: Noncanonical Ideas From Neural Stem Cell Biology

“…The involvement of RBPJ-k and the induction of Hes1 are often used as indicators of Notch activation. RBPJ-k and Hes1 involvement typically denote the operation of caNotch signaling (70)(71)(72) (Fig. 2), although RBPJ-k-independent functions of Notch have also been reported (but also Notch-independent RBPJ-k functions).…”

Voie de signalisation Notch et développement précoce des mammifères

“…Comment expliquer alors que les gènes codant pour les principaux acteurs de cette voie sont exprimés (certains de façon dynamique) dans l'ovocyte et/ou l'embryon pré-implantatoire [10,11] ? Une première possibilité résulte de la présence de transcrits ovocytaires qui masqueraient, chez des embryons mutants pour des gènes de la voie Notch, un rôle éventuel de cette [13,14], renforçant ainsi la notion que la voie Notch n'est pas indispensable pour le développement pré-implantatoire chez la souris (Figure 1). Dans ce contexte, le phénotype de létalité péri-implantatoire des souris mutantes pour Brainiac et mNotchless est tout à fait intrigant [15,16].…”