Article

Koo, B. K. et al. Mind bomb 1 is essential for generating functional Notch ligands to activate Notch. Development 132, 3459-3470

Department of Biology, Chungnam National University, Daiden, Daejeon, South Korea
Development (Impact Factor: 6.46). 09/2005; 132(15):3459-70. DOI: 10.1242/dev.01922
Source: PubMed

ABSTRACT

The Delta-Notch signaling pathway is an evolutionarily conserved intercellular signaling mechanism essential for cell fate specification. Mind bomb 1 (Mib1) has been identified as a ubiquitin ligase that promotes the endocytosis of Delta. We now report that mice lacking Mib1 die prior to embryonic day 11.5, with pan-Notch defects in somitogenesis, neurogenesis, vasculogenesis and cardiogenesis. The Mib1-/- embryos exhibit reduced expression of Notch target genes Hes5, Hey1, Hey2 and Heyl, with the loss of N1icd generation. Interestingly, in the Mib1-/- mutants, Dll1 accumulated in the plasma membrane, while it was localized in the cytoplasm near the nucleus in the wild types, indicating that Mib1 is essential for the endocytosis of Notch ligand. In accordance with the pan-Notch defects in Mib1-/- embryos, Mib1 interacts with and regulates all of the Notch ligands, jagged 1 and jagged 2, as well as Dll1, Dll3 and Dll4. Our results show that Mib1 is an essential regulator, but not a potentiator, for generating functional Notch ligands to activate Notch signaling.

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Available from: Ki-Jun Yoon, Jul 09, 2015
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    • "The activity of Dll1 is known to be regulated by ubiquitylation of its intracellular domain by the E3 ubiquitin-ligase Mindbomb1 (Koo et al., 2005Koo et al., , 2007Lai, 2002;Weinmaster and Fischer, 2011). Dll1 lacking the intracellular domain reaches the membrane but cannot activate Notch receptors in neighboring cells (Heuss et al., 2008;Nichols et al., 2007). "
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    • "and NP_065825.1 accession numbers, respectively). Mib1 is an E3 ubiquitin ligase localized to the PSD (Choe et al., 2007) that promotes Notch signaling by regulating endocytosis of the Notch ligands Delta (Koo et al., 2005a) and Jagged/Serrate (Lai et al., 2005; Le Borgne et al., 2005; Koo et al., 2007). Although Mib1 is important for neuronal differentiation in both the central (Haddon et al., 1998; Ossipova et al., 2009; Yamamoto et al., 2010) and peripheral (Kang et al., 2013) nervous systems, we did not observe differences in the sizes of the ventral nerve cord or muscles in mib1 mutants (data not shown). "
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    • "Author's personal copy surface in an 'activated' form in a mind bomb-dependent manner (Figure 17.3(b); Heuss et al., 2008). This activated Delta can now bind to Notch in neighboring cells and endocytose the NECD (Parks et al., 2000; Itoh et al., 2003; Koo et al., 2005; Chitnis, 2006). Trans-endocytosis of NECD in the ligand-presenting cell initiates a rapid series of sequential proteolytic cleavage (Figure 17.3(b)) events on the remaining N-terminus of Notch (S2 cleavage, ADAMs, etc.) in the signal-receiving cell. "
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