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Itoh, M, Kim, CH, Palardy, G, Oda, T, Jiang, YJ, Maust, D, Yeo, SY, Lorick, K, Wright, GJ, Ariza-McNaughton, L, Weissman, AM, Lewis, J, Chandrasekharappa, SC and Chitnis, AB (2003) Mind bomb is a ubiquitin ligase that is essential for efficient activation of Notch signaling by Delta. Dev. Cell 4:67-82


Lateral inhibition, mediated by Notch signaling, leads to the selection of cells that are permitted to become neurons within domains defined by proneural gene expression. Reduced lateral inhibition in zebrafish mib mutant embryos permits too many neural progenitors to differentiate as neurons. Positional cloning of mib revealed that it is a gene in the Notch pathway that encodes a RING ubiquitin ligase. Mib interacts with the intracellular domain of Delta to promote its ubiquitylation and internalization. Cell transplantation studies suggest that mib function is essential in the signaling cell for efficient activation of Notch in neighboring cells. These observations support a model for Notch activation where the Delta-Notch interaction is followed by endocytosis of Delta and transendocytosis of the Notch extracellular domain by the signaling cell. This facilitates intramembranous cleavage of the remaining Notch receptor, release of the Notch intracellular fragment, and activation of target genes in neighboring cells.




Animals; Blotting, Western; Cell Differentiation; Endocytosis; Gene Expression Regulation; In Situ Hybridization; Intracellular Signaling Peptides and Proteins; Ligases/chemistry; Ligases/genetics; Ligases/metabolism; Membrane Proteins/genetics; Membrane Proteins/metabolism; Molecular Sequence Data; Neurons/cytology; Neurons/metabolism; Phenotype; Protein Structure, Tertiary; RNA, Messenger/genetics; RNA, Messenger/metabolism; Receptors, Notch; Signal Transduction; Spinal Cord/embryology; Spinal Cord/metabolism; Ubiquitin/metabolism; Ubiquitin-Protein Ligases; Zebrafish/embryology; Zebrafish/genetics; Zebrafish/metabolism; Zebrafish Proteins/chemistry; Zebrafish Proteins/genetics; Zebrafish Proteins/metabolism



Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status


GO:0007219: Notch signaling pathway



Figure 1. ngn1 and deltaA, which are involved in Notch signaling are not as effectively restricted in mind bomb mutant embryos. Additionally, mutant embryonic cells express more huC, which is characteristic of cells that escape lateral inhibition mediated by the Notch pathway.


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