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


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.

Download full-text


Available from: Ki-Jun Yoon, Jul 09, 2015
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Notch signaling is ubiquitously used to coordinate differentiation between adjacent cells across metazoans. Whereas Notch pathway components have been studied extensively, the effect of membrane distribution and dynamics of Notch receptors and ligands remains poorly understood. It is also unclear how cellular morphology affects these distributions and, ultimately, the signaling between cells. Here, we combine live-cell imaging and mathematical modeling to address these questions. We use a FRAP-TIRF assay to measure the diffusion and endocytosis rates of Delta-like 1 (Dll1) in mammalian cells. We find large cell-to-cell variability in the diffusion coefficients of Dll1 measured in single cells within the same population. Using a simple reaction-diffusion model, we show how membrane dynamics and cell morphology affect cell-cell signaling. We find that differences in the diffusion coefficients, as observed experimentally, can dramatically affect signaling between cells. Together, these results elucidate how membrane dynamics and cellular geometry can affect cell-cell signaling.
    Full-text · Article · Jan 2016 · Cell Reports
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The postsynaptic density (PSD) is a protein-rich network important for the localization of postsynaptic glutamate receptors (GluRs) and for signaling downstream of these receptors. Although hundreds of PSD proteins have been identified, many are functionally uncharacterized. We conducted a reverse genetic screen for mutations that affected GluR localization using Drosophila genes that encode homologs of mammalian PSD proteins. 42.8% of the mutants analyzed exhibited a significant change in GluR localization at the third instar larval neuromuscular junction (NMJ), a model synapse that expresses homologs of AMPA receptors. We identified the E3 ubiquitin ligase, Mib1, which promotes Notch signaling, as a regulator of synaptic GluR localization. Mib1 positively regulates the localization of the GluR subunits GluRIIA, GluRIIB, and GluRIIC. Mutations in mib1 and ubiquitous expression of Mib1 that lacks its ubiquitin ligase activity result in the loss of synaptic GluRIIA-containing receptors. In contrast, overexpression of Mib1 in all tissues increases postsynaptic levels of GluRIIA. Cellular levels of Mib1 are also important for the structure of the presynaptic motor neuron. While deficient Mib1 signaling leads to overgrowth of the NMJ, ubiquitous overexpression of Mib1 results in a reduction in the number of presynaptic motor neuron boutons and branches. These synaptic changes may be secondary to attenuated glutamate release from the presynaptic motor neuron in mib1 mutants as mib1 mutants exhibit significant reductions in the vesicle-associated protein cysteine string protein and in the frequency of spontaneous neurotransmission.
    Full-text · Article · Nov 2015 · Molecular and Cellular Neuroscience
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The history of Notch signaling goes back almost a century, to some of the earliest studies of Drosophila development. Since this time, Notch signaling has been found to underlie many evolutionary conserved developmental processes in multiple systems and across phyla. In particular, Notch signaling plays a key role in both invertebrate and vertebrate nervous system development. From the initial identification of its neurogenic phenotype in flies, through recently reported roles in adult mammalian neurogenesis, Notch is best known for mediating lateral inhibition, a process that simultaneously regulates neural differentiation and maintenance of progenitor pools. Here, the authors review these classic functions of Notch, focusing on contributions from higher order vertebrate neurogenic model systems that reveal conserved molecular regulatory pathways similar to those operating in Drosophila. In addition, the authors review Notch's roles in gliogenesis, embryonic stem cells, and exciting new roles in diversifying neuronal subtypes, regulating neuronal morphology, synaptic plasticity, and neuronal activity, revealing that Notch is not(ch) your ordinary signaling pathway.
    Full-text · Chapter · Dec 2013
Show more