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Ubiquitylation-independent activation of Notch signalling by Delta.

ABSTRACT: Ubiquitylation (ubi) by the E3-ligases Mindbomb1 (Mib1) and Neuralized (Neur) is required for activation of the DSL ligands Delta (Dl) and Serrate (Ser) to activate Notch signalling. These ligases transfer ubiquitin to lysines of the ligands' intracellular domains (ICDs), which sends them into an Epsin-dependent endocytic pathway. Here, we have tested the requirement of ubi of Dl for signalling. We found that Dl requires ubi for its full function, but can also signal in two ubi-independent modes, one dependent and one independent of Neur. We identified two neural lateral specification processes where Dl signals in an ubi-independent manner. Neur, which is needed for these processes, was shown to be able to activate Dl in an ubi-independent manner. Our analysis suggests that one important role of DSL protein ubi by Mib1 is their release from cis-inhibitory interactions with Notch, enabling them to trans-activate Notch on adjacent cells.

SUBMITTER: Berndt N

PROVIDER: S-EPMC5675594 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Ubiquitylation-independent activation of Notch signalling by Delta.

Berndt Nicole N Seib Ekaterina E Kim Soya S Troost Tobias T Lyga Marvin M Langenbach Jessica J Haensch Sebastian S Kalodimou Konstantina K Delidakis Christos C Klein Thomas T

eLife 20170929

Ubiquitylation (ubi) by the E3-ligases Mindbomb1 (Mib1) and Neuralized (Neur) is required for activation of the DSL ligands Delta (Dl) and Serrate (Ser) to activate Notch signalling. These ligases transfer ubiquitin to lysines of the ligands' intracellular domains (ICDs), which sends them into an Epsin-dependent endocytic pathway. Here, we have tested the requirement of ubi of Dl for signalling. We found that Dl requires ubi for its full function, but can also signal in two ubi-independent modes ...[more]

PMID: 28960177

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Project description:Building the complex vertebrate nervous system involves the regulated production of neurons and glia while maintaining a progenitor cell population. Neurogenesis starts asynchronously in different regions of the embryo and occurs over a long period of time, allowing progenitor cells to be exposed to multiple extrinsic signals that regulate the production of different cell types. Notch-mediated cell-cell signalling is one of the mechanisms that maintain the progenitor pool, however, little is known about how the timing of Notch activation is related to the cell cycle and the distinct modes of cell division that generate neurons. An essential tool with which to investigate the role of Notch signalling on cell by cell basis is the development a faithful reporter of Notch activity.Here we present a novel reporter for Notch activity based on the promoter of the well characterised Notch target chick Hes5-1, coupled with multiple elements that confer instability, including a destabilized nuclear Venus fluorescent protein and the 3' untranslated region (UTR) of Hes5-1. We demonstrate that this reporter faithfully recapitulates the endogenous expression of Hes5-1 and that it robustly responds to Notch activation in the chick neural tube. Analysis of the patterns of Notch activity revealed by this reporter indicates that although Notch is most frequently activated prior to mitosis it can be activated at any time within the cell cycle. Notch active progenitors undergoing mitosis generate two daughters that both continue to experience Notch signalling. However, cells lacking Notch activity before and during mitosis generate daughters with dissimilar Notch activity profiles.A novel Notch reporter with multiple destabilisation elements provides a faithful read-out of endogenous Notch activity on a cell-by-cell basis, as neural progenitors progress through the cell cycle in the chick neural tube. Notch activity patterns in this cell population provide evidence for distinct Notch signalling dynamics underlying different cell division modes and for the involvement of random initiation of Notch signalling within the neuroepithelium. These findings highlight the importance of single-cell analysis in the study of the complexity of Notch activity and provide new insights into the mechanisms underlying cell fate decisions in neural progenitors.

Dataset Information

Ubiquitylation-independent activation of Notch signalling by Delta.

Publications

Ubiquitylation-independent activation of Notch signalling by Delta.

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