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Investigating the trafficking and activity of the gamma-secretase complex

Supervisor: Sarah Bray (with Maria Gomez-Lamarca)

Notch signalling is a highly conserved pathway in the animal kingdom that controls developmental decisions in multiple tissue types and at different stages of development. Functions of the Notch pathway include maintenance of stem/progenitor cells, regulation of cell fates and organizing patterns of growth. Aberrant Notch activity underlies a wide range of human disorders including cancer.

Following activation by its ligands, the Notch receptor is cleaved in a two-step process. The second cleavage is mediated by the gamma-secretase complex and releases the Notch intracellular domain (NICD), which migrates to the nucleus and promotes transcription. Activation of Notch in the absence of ligands has also been identified in pathological conditions. This is associated with perturbations in Notch trafficking and also requires the gamma-secretase complex.

Mechanisms regulating the location and/or activity of the gamma-secretase complex are therefore of major importance for Notch activity. Defects in gamma-secretase are also be highly relevant for its processing of APP, a key factor in the onset of Alzheimer’s disease. As Drosophila has a single homologue of each component of the multi-subunit complex (unlike mammals), it offers a highly tractable model to investigate its regulation. The aim of the project will be to use CRISPR-Cas9 genome editing to introduce fluorescent tags into subunits of the complex and to use confocal and super resolution microscopy, in conjunction with genetic tools, to discover where the complex is located and how its behaviour is affected by perturbations to trafficking and signaling

Aims

  1. Studying the distribution of the gamma-secretase complex within the endocytic pathway and Identifying the degree of co-localization with Notch

  2. Investigate the consequences on the gamma-secretase complex when key endocytic regulators are depleted.

  3. Identify whether there are conditions that lead to the gamma-secretase complex to become dissociated.

 

Relevant references

Bray, SJ (2016) Notch signalling in Context. Nature Reviews in Molecular and Cellular Biology 7(11):722-735

Gomez-Lamarca MJ, Snowdon LA, Seib E, Klein T, Bray SJ (2015) Rme-8 depletion perturbs Notch recycling and predisposes to pathogenic signaling. J Cell Biol 210(2): 303-318

 

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