Isolation of a Murine Homologue of the Drosophila neuralized Gene, a Gene Required for Axonemal Integrity in Spermatozoa and Terminal Maturation of the Mammary Gland

Howard Hughes Medical Institute and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 12/2001; 21(21):7481-94. DOI: 10.1128/MCB.21.21.7481-7494.2001
Source: PubMed


The Drosophila neuralized gene shows genetic interactions with Notch, Enhancer of split, and other neurogenic genes and is thought to be involved in cell fate specification in the central nervous system and the
mesoderm. In addition, a human homologue of the Drosophila neuralizedgene has been described as a potential tumor suppressor gene in malignant astrocytomas. We have isolated a murine homologue
of theDrosophila and human Neuralized genes and, in an effort to understand its physiological function, derived mice with a targeted deletion of this gene. Surprisingly,
mice homozygous for the introduced mutation do not show aberrant cell fate specifications in the central nervous system or
in the developing mesoderm. This is in contrast to mice with targeted deletions in other vertebrate homologues of neurogenic
genes such as Notch, Delta, andCbf-1. Male Neuralized null mice, however, are sterile due to a defect in axoneme organization in the spermatozoa that leads to highly compromised
tail movement and sperm immotility. In addition, female Neuralized null animals are defective in the final stages of mammary gland maturation during pregnancy.

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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.
    Full-text · Article · Jul 2012 · PLoS ONE
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    • "In vertebrates, Mind bomb, but not Neuralized, is required for Notch signaling Studies in flies have demonstrated clearly a critical role for Neur in Notch signaling, which involves ligand ubiquitylation and endocytosis in the generation of a productive signal. It was therefore surprising when two groups reported in 2001 that mice lacking the mammalian neur homolog (neur1) do not display any obvious Notch-like developmental phenotypes (Ruan et al., 2001; Vollrath et al., 2001). Moreover, these mice are viable and fertile, which is in strong contrast to the mid-gestation lethality reported for gene knockouts of core components of the Notch signaling pathway. "
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    ABSTRACT: In the first volume of Developmental Cell, it was reported that the classic Drosophila neurogenic gene neuralized encodes a ubiquitin ligase that monoubiquitylates the Notch ligand Delta, thus promoting Delta endocytosis. A requirement for ligand internalization by the signal-sending cell, although counterintuitive, remains to date a feature unique to Notch signaling. Ten years and many ubiquitin ligases later, we discuss sequels to these three papers with an eye toward reviewing the development of ideas for how ligand ubiquitylation and endocytosis propel Notch signaling.
    Preview · Article · Jul 2011 · Developmental Cell
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    • "However, subsequent analyses indicated that both the expression and localization of Neur are enhanced in signal-sending cells (Bardin and Schweisguth, 2006; Le Borgne and Schweisguth, 2003b; Morel et al., 2003) and that Neur functions nonautonomously in cell fate decisions regulated by Notch signaling (Pavlopoulos et al., 2001), providing support for the idea that Neur-induced endocytosis functions directly to stimulate ligand signaling activity. Although studies in flies and frogs support a role for Neur in generating a productive signal and/or regulating cell surface levels, gene targeting of the mammalian Neur homolog yields viable mice lacking obvious Notch developmental defects (Ruan et al., 2001; Vollrath et al., 2001). This surprising finding suggested that mammalian Neur might not be an essential component of the Notch signaling pathway or alternatively, additional E3 ubiqutin ligases exist to modify DSL ligands and facilitate Notch activation. "
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    ABSTRACT: The Notch signaling pathway regulates a diverse array of cell types and cellular processes and is tightly regulated by ligand binding. Both canonical and noncanonical Notch ligands have been identified that may account for some of the pleiotropic nature associated with Notch signaling. This review focuses on the molecular mechanisms by which Notch ligands function as signaling agonists and antagonists, and discusses different modes of activating ligands as well as findings that support intrinsic ligand signaling activity independent of Notch. Post-translational modification, proteolytic processing, endocytosis and membrane trafficking, as well as interactions with the actin cytoskeleton may contribute to the recently appreciated multifunctionality of Notch ligands. The regulation of Notch ligand expression by other signaling pathways provides a mechanism to coordinate Notch signaling with multiple cellular and developmental cues. The association of Notch ligands with inherited human disorders and cancer highlights the importance of understanding the molecular nature and activities intrinsic to Notch ligands. Oncogene (2008) 27, 5148-5167; doi:10.1038/onc.2008.229.
    Full-text · Article · Oct 2008 · Oncogene
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