Award details

Intracellular and extracellular regulation of Notch localisation and signalling

Reference	BB/C503162/1
Principal Investigator / Supervisor	Dr Martin Baron
Co-Investigators / Co-Supervisors
Institution	The University of Manchester
Department	Life Sciences
Funding type	Research
Value (£)	256,477
Status	Completed
Type	Research Grant
Start date	01/01/2005
End date	30/09/2009
Duration	57 months

Abstract

Notch is an essential developmental gene, which encodes a signalling receptor used repeatedly during development to mediate local cell-cell signals that refine spatial values to a high resolution and direct the differentiation of appropriate cell types. Notch also regulates the maintenance/self renewal and differentiation of stem cells making it strategically important to understand the nature of its signalling pathway. In addition to its biological significance, understanding Notch may be of commercial importance since its manipulation provides a route to tailoring of desired cell fates. If this is to be realised then understanding how to manipulate the level of Notch signalling will be an important goal. Notch has a conserved signalling pathway involving a ligand-induced cleavage, which removes the extracellular domain followed by a constitutive cleavage within the transmembrane region, which releases a soluble intracellular domain for transport to the nucleus, where it regulates gene expression of specific target genes such as wingless. However in addition to the ligands, other extracellular and intracellular factors regulate the level of the signal. We have shown that a key regulatory step is in the early endosome where membrane proteins are sorted either to the late endosome or into a recycling pathway. The former may lead to degradation and the latter may return proteins to the cell surface. Sorting in the secretory pathway, between trafficking to the cell surface or through shunt pathway direct to the endosomal system, may also be involved in regulating Notch availability for activation. We have demonstrated that both extracellular and intracellular regions of notch are required to mediate proper localisation at the apical junctions. This project will examine in detail the localisation and trafficking routes of Notch in vivo using Drosophila wing and follicle epithelia as model systems. We will determine how perturbation and regulation of Notch trafficking routes modulates Notch activity. In particular we will determine how internalisation of Notch to the early endosome can lead to an upregulated signal. We will next identify mechanisms regulating notch accumulation at the apical cell junctions, considering whether sorting in both the secretory and endocytic pathways may regulate Notch surface availability. We will map the regions of Notch that are necessary and sufficient for these regulatory interactions, and identify proteins and cross-talking signals that regulate Notch trafficking and cell localisation. The latter will include an investigation of the mechanism by which Notch ligands, Delta and Serrate, can down-regulate Notch when expressed in the same cell, and will determine whether the many cross-regulatory interactions between Notch and components of the Wingless signalling pathway also involve trafficking regulation.

Summary

unavailable

Committee	Closed Committee - Biochemistry & Cell Biology (BCB)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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