Membrane traffic between organelles is essential for secretion, uptake of nutrients, and the regulation of signal transduction. At the centre of this system lies the Golgi apparatus – the major sorting station that directs traffic from the endoplasmic reticulum (ER) to the rest of the cell and links the secretory and endocytic pathways.
The Golgi is a stack of flat compartments arranged from cis to trans. Newly-made proteins are carried by vesicles from the ER to the cis Golgi and then pass through the stack to exit from the trans Golgi for destinations elsewhere in the cell. Our lab has identified many proteins that help to organise the Golgi and its membrane trafficking pathways. In recent years, rare mutations in the genes for several of these proteins have been found to cause defects in the development of the brain and other tissues.
The formation of tissues can be modelled in vitro using organoids (mini organs) grown from stem cells. The PhD project is to investigate the role of particular Golgi proteins in tissue function, and in particular in neurodevelopment by using brain organoids. One focus will be a protein called YIPF5 that forms a complex with three other proteins, one of which we discovered. This complex plays a major, but poorly understood, role in secretion. Mutations in YIPF5, or in two of its binding partners, have been found in patients with microcephaly, epilepsy and diabetes (MEDS) syndrome. The project will be to use cell biological and biochemical methods, including advanced light microscopy and proteomics, to investigate the function of the YIPF5 complex. In addition, CRISPR-Cas9 genome engineering of stem cells will be used to examine the effect that mutations in the complex have on the development of brain organoids and hence determine the role of the complex in developing tissues.