Crosstalk of the cell-surface membrane system
The formation of neural network is essential for building a nerve system and to maintain its dynamic function. Neuronal cells extend their axons to connect to dendrites of partner neurons. The process is facilitated by axonal migration and controlled by the balance of the search for partner neurons vs the locking of axon-dendrite connections. This balance is maintained by two signaling pathways relying on the integrin receptor (mode of neurite migration) and the semaphorin receptor (mode of axon-dendrite locking). The inter-regulation between both pathways is mediated by the intracellular signaling factor Rap1. However, the mechanism of this interconnection is unknown.
This PhD project aims to elucidate the nature of this crosstalk using a bottom-up reconstitution of integrin, semaphorin and Rap1 by developing a cell-surface mimicking membrane system. We aim to establish a functional membrane system that allows us to control the two modes, i.e. attachment/detachment of two neighboring membranes representing dendrite and axon connections. The uniqueness of the project lies in the exact control of communication through membranes by the bottom-up strategy, which would be otherwise extremely challenging to elucidate. Moreover, the system will allow us to probe receptor interactions using biophysical, light microscopic as well as cryo-EM methods to understand the underlying principles of neural network formation and neuronal regeneration.
Our collaborative team has expertise in a wide variety of interdisciplinary techniques to facilitate the proposed PhD research, such as X-ray crystallography, cryo-EM, biophysical analysis, membrane biology and light microscopy. Mizuno lab is leading in the use of cryo-EM in combination with cellular methods to visualize cell shape formations controlled by the integrin signaling pathway and the remodeling of cytoskeleton components. Jones lab has a long-standing interest in axon guidance and structural biology of membrane proteins. Yvonne Jones co-heads the Structural Biology Division of the Wellcome Centre for Human Genetics at the University of Oxford.
This project will give a candidate a tremendous opportunity to apply cutting-edge in vitro reconstitution methods in the field of structural- and neuro- biology.