New signaling mechanisms in myelination

The development and function of the tissues in our body depend on the continued interaction between the cells that make up the tissue. Cells are continuously talking to each other through molecules they send out or display on their surface. Neighbouring cells need to be able to sense and respond to these signals, so they have receptors for them. The signals and receptors come in many different varieties, and understanding their function is key to understanding animal and plant development.
In this work we will examine the role of a signal and receptor molecule that are important for the development and function of the insulating layer (called the myelin sheath) that surrounds many of the nerve cells. These nerves trigger our senses and steer our muscles and the myelin sheath is important for the fast relay of information along our nerves. Highly similar signalling and receptor molecules exist in other parts of the brain where they fulfil other important functions, but it is not known if they all act in a similar way. We aim to elucidate how these signal:receptor molecules work in myelin formation and compare it with what we know about related proteins in other parts of the brain. This will give us deeper insight into the way these molecules work and how disturbances of these signals lead to developmental defects and neurological disease.

We discovered a novel molecular interaction between Schwann cells and neurons that is essential for efficient axonal ensheathment and myelination in the peripheral nervous system (PNS). This interaction involves the ligand LGI4, a protein secreted by Schwann cells and its axonal transmembrane receptor ADAM22. LGI4 is a member of a small family of four closely related proteins implicated in synaptic plasticity and epilepsy, whereas ADAM22 belongs, together with ADAM23 and ADAM11, to a subgroup of the larger family of integrin receptors and metalloproteinases that are involved in diverse developmental processes including cell migration, axonal path finding and processing of growth factors.

We hypothesize that LGI4-induced assembly of ADAM22 protein complexes in the axonal membrane acts in trans to serve as a ligand for Integrins or other proteins embedded in the apposing Schwann cell membrane. Also, assembly of such LGI4:ADAM22 protein complexes may involve interactions through the highly conserved ADAM22 cytoplasmic domain.

Here, we aim to identify the intracellular signalling pathways in Schwann cells regulated by the LGI4:ADAM22 signal (Aim 1). To establish a link between these intracellular signalling pathways and the LGI4:ADAM22 complex we will identify proteins at the Axon-Schwann cell apposition with which the complex interacts (Aim 2). Further, we will examine the role of the intra-axonal domain of ADAM22 and identify axonal proteins that interact with this domain (Aim 3).

The insights gained from this work on the mechanism and role of LGI4:ADAM22 interactions in axonal myelination in the PNS will have wider implications for our understanding of LGI4 and ADAM22 proteins in other parts of the nervous system, such as the cerebellum where both LGI4 and ADAM22 are highly expressed. Moreover, these insights will generate testable hypotheses about the role of other members of the LGI and ADAM family in nervous system development and function.

This research will have considerable impact in several areas.

Scientifically, this work will provide novel conceptual insights into the way LGI and non-metalloproteinase ADAM proteins regulate morphological and structural adaptations at cellular appositions. It will identify novel molecules involved in these functions, shedding light on the extraordinary specificity of LGI:ADAM interactions.

Technologically, this work contributes to the full development of the relatively novel BioID strategy to identify interacting proteins, thus increasing the capacity of our analytical repertoire. We will establish and validate conditional expression of transgenes in in vitro neuron-Schwann cell co-cultures.

Our continuous efforts to further develop our neuron-Schwann cell co-culture system will refine our design of transgenic constructs and will help to reduce the number of experimental animals used in this study, thus contributing directly to the 3Rs.

Through this work we will forge collaborations within the larger University of Edinburgh neuroscience and cell biology community and beyond and establish our laboratory within the larger UK research community

At the end of this project we will have trained one research assistant, one PhD student and at least two MSc students.

Through our teaching in diverse neuroscience programmes, this research directly benefits students at all levels of academic training.