Mind bomb1 is a ubiquitin ligase essential for mouse embryonic development and Notch signaling

ABSTRACT The Notch signaling pathway controls several cell fate decisions during lymphocyte development, from T-cell lineage commitment to the peripheral differentiation of B and T lymphocytes. Deltex-1 is a RING finger ubiquitin ligase which is conserved from Drosophila to humans and has been proposed to be a regulator of Notch signaling. Its pattern of lymphoid expression as well as gain-of-function experiments suggest that Deltex-1 regulates both B-cell lineage and splenic marginal-zone B-cell commitment. Deltex-1 was also found to be highly expressed in germinal-center B cells. To investigate the physiological function of Deltex-1, we generated a mouse strain lacking the Deltex-1 RING finger domain, which is essential for its ubiquitin ligase activity. Deltex-1Δ/Δ mice were viable and fertile. A detailed histological analysis did not reveal any defects in major organs. T- and B-cell development was normal, as were humoral responses against T-dependent and T-independent antigens. These data indicate that the Deltex-1 ubiquitin ligase activity is dispensable for mouse development and immune function. Possible compensatory mechanisms, in particular those from a fourth Deltex gene identified during the course of this study, are also discussed.

Download Full-text

The NHR1 Domain of Neuralized Binds Delta and Mediates Delta Trafficking and Notch Signaling

Molecular Biology of the Cell ◽

10.1091/mbc.e06-08-0753 ◽

2007 ◽

Vol 18 (1) ◽

pp. 1-13 ◽

Cited By ~ 26

Author(s):

Cosimo Commisso ◽

Gabrielle L. Boulianne

Keyword(s):

Plasma Membrane ◽

Notch Signaling ◽

Ubiquitin Ligase ◽

Protein Interactions ◽

Neural Development ◽

Ring Domain ◽

Protein Protein Interactions ◽

Necessary And Sufficient ◽

Conserved Residue ◽

Notch Ligands

Notch signaling, which is crucial to metazoan development, requires endocytosis of Notch ligands, such as Delta and Serrate. Neuralized is a plasma membrane-associated ubiquitin ligase that is required for neural development and Delta internalization. Neuralized is comprised of three domains that include a C-terminal RING domain and two neuralized homology repeat (NHR) domains. All three domains are conserved between organisms, suggesting that these regions of Neuralized are functionally important. Although the Neuralized RING domain has been shown to be required for Delta ubiquitination, the function of the NHR domains remains elusive. Here we show that neuralized1, a well-characterized neurogenic allele, exhibits a mutation in a conserved residue of the NHR1 domain that results in mislocalization of Neuralized and defects in Delta binding and internalization. Furthermore, we describe a novel isoform of Neuralized and show that it is recruited to the plasma membrane by Delta and that this is mediated by the NHR1 domain. Finally, we show that the NHR1 domain of Neuralized is both necessary and sufficient to bind Delta. Altogether, our data demonstrate that NHR domains can function in facilitating protein–protein interactions and in the case of Neuralized, mediate binding to its ubiquitination target, Delta.

Download Full-text

B-1 lymphoid cells develop independently of Notch signaling during mouse embryonic development

10.1101/2020.11.09.375634 ◽

2020 ◽

Author(s):

Nathalia Azevedo ◽

Elisa Bertesago ◽

Ismail Ismailoglu ◽

Michael Kyba ◽

Michihiro Kobayashi ◽

...

Keyword(s):

Stem Cells ◽

Embryonic Development ◽

Blood Cell ◽

Notch Signaling ◽

Embryonic Stem ◽

Cell Types ◽

Lymphoid Cells ◽

Lineage Specification ◽

Hematopoietic Stem

AbstractThe in vitro generation from pluripotent stem cells (PSCs) of different blood cell types, in particular those that are not replenished by hematopoietic stem cells (HSCs) like fetal-derived tissue-resident macrophages and innate-like lymphocytes, is of a particular interest. In order to succeed in this endeavor, a thorough understanding of the pathway interplay promoting lineage specification for the different blood cell types is needed. Notch signaling is essential for the HSC generation and their derivatives, but its requirement for tissue-resident immune cells is unknown. Using mouse embryonic stem cells (mESCs) to recapitulate murine embryonic development, we have studied the requirement for Notch signaling during the earliest B-lymphopoiesis and found that Rbpj-deficient mESCs are able to generate B-1 cells. Their Notch-independence was confirmed in ex vivo experiments using Rbpj-deficient embryos. In addition, we found that upregulation of Notch signaling was needed for the emergence of B-2 lymphoid cells. Taken together, these findings indicate that control of Notch signaling dosage is critical for the different B-cell lineage specification and provides pivotal information for their in vitro generation from PSCs for therapeutic applications.

Download Full-text

Multi-Faceted Notch in Allergic Airway Inflammation

International Journal of Molecular Sciences ◽

10.3390/ijms20143508 ◽

2019 ◽

Vol 20 (14) ◽

pp. 3508

Author(s):

Miao-Tzu Huang ◽

Chiao-Juno Chiu ◽

Bor-Luen Chiang

Keyword(s):

Embryonic Development ◽

Notch Signaling ◽

Airway Inflammation ◽

Cell Activity ◽

Adult Life ◽

Allergic Airway Inflammation ◽

T Cell Subsets ◽

Cell Fate Decisions ◽

Physiological Processes

Notch is an evolutionarily conserved signaling family which iteratively exerts pleiotropic functions in cell fate decisions and various physiological processes, not only during embryonic development but also throughout adult life. In the context of the respiratory system, Notch has been shown to regulate ciliated versus secretory lineage differentiation of epithelial progenitor cells and coordinate morphogenesis of the developing lung. Reminiscent of its role in development, the Notch signaling pathway also plays a role in repair of lung injuries by regulation of stem cell activity, cell differentiation, cell proliferation and apoptosis. In addition to functions in embryonic development, cell and tissue renewal and various physiological processes, including glucose and lipid metabolism, Notch signaling has been demonstrated to regulate differentiation of literally almost all T-cell subsets, and impact on elicitation of inflammatory response and its outcome. We have investigated the role of Notch in allergic airway inflammation in both acute and chronic settings. In this mini-review, we will summarize our own work and recent advances on the role of Notch signaling in allergic airway inflammation, and discuss potential applications of the Notch signaling family in therapy for allergic airway diseases.

Download Full-text

Notch signaling: Key role in intrauterine infection/inflammation, embryonic development, and white matter damage?

Journal of Neuroscience Research ◽

10.1002/jnr.22229 ◽

2009 ◽

pp. NA-NA ◽

Cited By ~ 2

Author(s):

Tian-Ming Yuan ◽

Hui-Min Yu

Keyword(s):

White Matter ◽

Embryonic Development ◽

Notch Signaling ◽

Intrauterine Infection ◽

White Matter Damage

Download Full-text

Wnt regulation: exploring Axin-Disheveled interactions and defining mechanisms by which the SCF E3 ubiquitin ligase is recruited to the destruction complex

Molecular Biology of the Cell ◽

10.1091/mbc.e19-11-0647 ◽

2020 ◽

Vol 31 (10) ◽

pp. 992-1014 ◽

Cited By ~ 2

Author(s):

Kristina N. Schaefer ◽

Mira I. Pronobis ◽

Clara E. Williams ◽

Shiping Zhang ◽

Lauren Bauer ◽

...

Keyword(s):

Stem Cell ◽

Embryonic Development ◽

Wnt Signaling ◽

Ubiquitin Ligase ◽

Human Cancer ◽

E3 Ubiquitin Ligase ◽

E3 Ligase ◽

Adult Stem Cell ◽

Cell Homeostasis ◽

Test Models

Wnt signaling plays key roles in embryonic development and adult stem cell homeostasis and is altered in human cancer. We explore β-catenin transfer from the destruction complex to the E3 ligase, and test models suggesting Dishevelled and APC2 compete for association with Axin.

Download Full-text

RBP-Jκ-Dependent Notch Signaling Is Dispensable for Mouse Early Embryonic Development

Molecular and Cellular Biology ◽

10.1128/mcb.00319-06 ◽

2006 ◽

Vol 26 (13) ◽

pp. 4769-4774 ◽

Cited By ~ 33

Author(s):

Céline Souilhol ◽

Sarah Cormier ◽

Kenji Tanigaki ◽

Charles Babinet ◽

Michel Cohen-Tannoudji

Keyword(s):

Embryonic Development ◽

Notch Signaling ◽

Signaling Pathway ◽

Cell Fate ◽

Notch Pathway ◽

Notch Signaling Pathway ◽

Preimplantation Embryos ◽

Cell Fate Specification ◽

Fate Specification ◽

Evolutionarily Conserved

ABSTRACT The Notch signaling pathway is an evolutionarily conserved signaling system which has been shown to be essential in cell fate specification and in numerous aspects of embryonic development in all metazoans thus far studied. We recently demonstrated that several components of the Notch signaling pathway, including the four Notch receptors and their five ligands known in mammals, are expressed in mouse oocytes, in mouse preimplantation embryos, or both. This suggested a possible implication of the Notch pathway in the first cell fate specification of the dividing mouse embryo, which results in the formation of the blastocyst. To address this issue directly, we generated zygotes in which both the maternal and the zygotic expression of Rbpsuh, a key element of the core Notch signaling pathway, were abrogated. We find that such zygotes give rise to blastocysts which implant and develop normally. Nevertheless, after gastrulation, these embryos die around midgestation, similarly to Rbpsuh-null mutants. This demonstrates that the RBP-Jκ-dependent pathway, otherwise called the canonical Notch pathway, is dispensable for blastocyst morphogenesis and the establishment of the three germ layers, ectoderm, endoderm, and mesoderm. These results are discussed in the light of recent observations which have challenged this conclusion.

Download Full-text

Expression of a novel zebrafish zinc finger gene,gli2b, is affected in Hedgehog and Notch signaling related mutants during embryonic development

Developmental Dynamics ◽

10.1002/dvdy.20242 ◽

2005 ◽

Vol 232 (2) ◽

pp. 479-486 ◽

Cited By ~ 15

Author(s):

Zhiyuan Ke ◽

Alexander Emelyanov ◽

Simon Eng Seng Lim ◽

Vladimir Korzh ◽

Zhiyuan Gong

Keyword(s):

Embryonic Development ◽

Notch Signaling ◽

Zinc Finger ◽

Zinc Finger Gene

Download Full-text

Cyclin B3 activates the Anaphase-Promoting Complex/Cyclosome in meiosis and mitosis

10.1101/2020.06.05.136291 ◽

2020 ◽

Author(s):

Damien Garrido ◽

Mohammed Bourouh ◽

Éric Bonneil ◽

Pierre Thibault ◽

Andrew Swan ◽

...

Keyword(s):

Embryonic Development ◽

Chromosome Segregation ◽

Ubiquitin Ligase ◽

Anaphase Promoting Complex ◽

Cells In Culture ◽

Cyclin B3 ◽

Mitosis And Meiosis ◽

In Cells

ABSTRACTIn mitosis and meiosis, chromosome segregation is triggered by the Anaphase-Promoting Complex/Cyclosome (APC/C), a multi-subunit ubiquitin ligase that targets proteins for degradation, leading to the separation of chromatids. APC/C activation requires phosphorylation of its APC3 and APC1 subunits, which allows the APC/C to bind its Cdc20 co-activator. The identity of the kinase(s) responsible for APC/C activation in vivo is unclear. Cyclin B3 is required for meiotic anaphase in flies, worms and vertebrates, but whether it activates the APC/C is unclear. We found that Drosophila Cyclin B3 (CycB3) collaborates with PP2A-B55/Tws in embryonic development, indicating that CycB3 also promotes anaphase in mitosis. Moreover, CycB3 promotes APC/C activity and anaphase in cells in culture. We show that CycB3 physically associates with the APC/C, is required for phosphorylation of APC3, and promotes APC/C association with its co-activators. We propose that CycB3-Cdk1 directly phosphorylates the APC/C to activate it in both meiosis and mitosis.

Download Full-text