Understanding the inheritance of the Endoplasmic Reticulum during cell division

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Strategic Research Priority: World Class BioscienceAbstract Division requires the precise segregation of the entire set of cellular structures. Despite this, studies of eukaryotic cell division have tended to focus on chromosomes segregation, while almost nothing is known about the way the ER is segregated at division. The aim of this project is to use advanced imaging technologies and biophysical techniques to remedy this to understand how the endoplasmic reticulum is properly formed and distributed between daughter cells during mitosis and divisions. Project The endoplasmic reticulum (ER) is a network of internal membranes that is continuous with the nuclear envelope, and that extends through the cytoplasm of all eukaryotic cells. Despite its importance, the mechanisms controlling the proper inheritance of this organelle at division remain largely unknown. During cell division, the ER must be remodelled, partitioned into daughter cells and reassembled into both a functional ER and a sealed nuclear envelope. The purpose of this PhD will be to characterize roles played by the cytoskeleton and a recently described membrane trafficking machinery called ESCRT, in ER shaping and inheritance, processes essential for proper organelle biogenesis. ESCRT is an ideal target for this analysis since it plays important roles in cytokinesis and endosomal sorting2. Moreover, ESCRT proteins have recently been shown to be involved in the formation of the nuclear envelope following mitotic exit3 and an evolutionary role for ESCRT in cellularisation has been proposed4. Disruption of ESCRT function brings about multiple failures in cell division - as such analysis of ESCRT function during this process is essential for our knowledge of how cells divide, and for the disease consequences of ESCRT loss, which include neurodegeneration and cancer. This protein complex is likely to be aided by the actin and microtubule cytoskeletons, which provide cellular membranes with a structural support, and guide the inheritance of other cytoplasmic organelles including mitochondria and Golgi. Thus, the student will also explore the differential role and localisation of actin isoforms in ER segregation at division5. This project will require a combination of biochemistry, molecular genetics, advanced cell biology (fixed- and live-cell imaging), correlative light and electron microscopy and computational reconstruction to perform a detailed analysis of ER shaping and inheritance during cell division and will examine defects in this process when ESCRT function, or cytoskeletal regulators, are compromised.