Abstract
BackgroundThe Notch signaling pathway is an evolutionarily conserved intercellular signaling module essential for cell fate specification that requires endocytosis of Notch ligands. Structurally distinct E3 ubiquitin ligases, Neuralized (Neur) and Mind bomb (Mib), cooperatively regulate the endocytosis of Notch ligands in Drosophila. However, the respective roles of the mammalian E3 ubiquitin ligases, Neur1, Neur2, Mib1, and Mib2, in mammalian development are poorly understood.Methodology/Principal FindingsThrough extensive use of mammalian genetics, here we show that Neur1 and Neur2 double mutants and Mib2−/− mice were viable and grossly normal. In contrast, conditional inactivation of Mib1 in various tissues revealed the representative Notch phenotypes: defects of arterial specification as deltalike4 mutants, abnormal cerebellum and skin development as jagged1 conditional mutants, and syndactylism as jagged2 mutants.Conclusions/SignificanceOur data provide the first evidence that Mib1 is essential for Jagged as well as Deltalike ligand-mediated Notch signaling in mammalian development, while Neur1, Neur2, and Mib2 are dispensable.
Highlights
The Notch signaling pathway is an evolutionarily conserved signaling module from nematode to human, which plays essential roles in pattern formation and cell fate determination through local cell-cell interactions [1]
It has been suggested that the endocytosis of Notch ligands in the signal-sending cells is required for the effective activation of Notch signaling [4]
Our results clearly demonstrate the obligatory role of Mib1 in the regulation of Notch ligands during mammalian development
Summary
The Notch signaling pathway is an evolutionarily conserved signaling module from nematode to human, which plays essential roles in pattern formation and cell fate determination through local cell-cell interactions [1]. Notch signaling is initiated by the interaction of the Notch receptors with their ligands, Delta [Deltalike (Dll) in mammals] and Serrate [Jagged (Jag) in mammals] [2,3] These interactions induce two sequential proteolytic cleavages of Notch receptor (S2 and S3 cleavages), and generate a soluble intracellular domain (Nicd) that translocates to the nucleus to form a transcriptional activator complex with Su(H)/CBF1/RBP-J. Two structurally distinct E3 ubiquitin ligases, Neuralized (Neur) and Mind bomb (Mib), regulate the endocytosis of the Notch ligand, Delta, in Drosophila and zebrafish, respectively [5,6,7,8,9]. Our data provide the first evidence that Mib is essential for Jagged as well as Deltalike ligand-mediated Notch signaling in mammalian development, while Neur, Neur, and Mib are dispensable
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