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.

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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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    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.
    Comprehensive Developmental Neuroscience: Patterning and Cell Type Specification in the Developing CNS and PNS, volume 1 edited by John LR Rubenstein, Pasko Rakic, 01/2013: chapter 17: pages 313-332; Academic Press, Oxford., ISBN: 9780123972651
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    • "Lastly, in this study, specific deletion of Mib1 in excitatory neurons using a CamKII-cre transgenic line caused decreased Notch signaling in the hippocampus, which was accompanied by hippocampus-dependent memory deficits and impaired L-LTP and LTD. Considering the nonautonomous role of Mib1 in signal-sending cells for the proper transduction of Notch signaling [15,21], both signal-sending cells and signal-receiving cells of Notch signaling are excitatory neurons in the hippocampus. In addition, coexistence of Mib1 and Jagged1 proteins in the synaptosome (Figure 1D) suggests that Notch-Notch ligand interaction might occur at excitatory synapses. "
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    ABSTRACT: Background Notch signaling is well recognized as a key regulator of the neuronal fate during embryonic development, but its function in the adult brain is still largely unknown. Mind bomb-1 (Mib1) is an essential positive regulator in the Notch pathway, acting non-autonomously in the signal-sending cells. Therefore, genetic ablation of Mib1 in mature neuron would give valuable insight to understand the cell-to-cell interaction between neurons via Notch signaling for their proper function. Results Here we show that the inactivation of Mib1 in mature neurons in forebrain results in impaired hippocampal dependent spatial memory and contextual fear memory. Consistently, hippocampal slices from Mib1-deficient mice show impaired late-phase, but not early-phase, long-term potentiation and long-term depression without change in basal synaptic transmission at SC-CA1 synapses. Conclusions These data suggest that Mib1-mediated Notch signaling is essential for long-lasting synaptic plasticity and memory formation in the rodent hippocampus.
    Molecular Brain 10/2012; 5(1):40. DOI:10.1186/1756-6606-5-40 · 4.90 Impact Factor
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    • "Recently, it was revealed that ligand internalization by endocytosis in the signal-sending cells is absolutely required for the initiation of Notch activation [17]. Four different E3 ubiquitin ligases, Mind bomb-1 (Mib1), Mib2, Neuralized-1 (Neur1), and Neur2 have been shown to regulate the endocytosis of Notch ligands in mice [18], [19], [20], [21], [22]; however, only Mib1 has been shown to play an obligatory role in the activation of Jag- as well as Dll-mediated Notch activation in vivo [23]. Therefore, cell-type-specific Mib1 conditional knockout mice have been known as excellent models for elucidating the role of Notch signaling in various contexts [24], [25], [26], [27], [28], [29]. "
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    ABSTRACT: In dendritic cell (DC)-CD4(+) T cell interaction, Notch signaling has been implicated in the CD4(+) T cell activation, proliferation, and subset differentiation. However, there has been a lot of debate on the exact role of Notch signaling. Here, we observed that expression of Mind bomb-1 (Mib1), a critical regulator of Notch ligands for the activation of Notch signaling, increases gradually as precursor cells differentiate into DCs in mice. To clarify the role of Mib1 in DC-CD4(+) T cell interactions, we generated Mib1-null bone marrow-derived DCs. These cells readily expressed Notch ligands but failed to initiate Notch activation in the adjacent cells. Nevertheless, Mib1-null DCs were able to prime the activation and proliferation of CD4(+) T cells, suggesting that Notch activation in CD4(+) T cells is not required for these processes. Intriguingly, stimulation of CD4(+) T cells with Mib1-null DCs resulted in dramatically diminished Th2 cell populations, while preserving Th1 cell populations, both in vitro and in vivo. Our results demonstrate that Mib1 in DCs is critical for the activation of Notch signaling in CD4(+) T cells, and Notch signaling reinforces Th2 differentiation, but is not required for the activation or proliferation of the CD4(+) T cells.
    PLoS ONE 07/2012; 7(4):e36359. DOI:10.1371/journal.pone.0036359 · 3.23 Impact Factor
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