PhD Studentship: The Role of AMIGO3 in the Formation and Repair of Myelination the Central Nervous System

Myelin, a fatty insulating sheath enwrapping axons in the nervous system, plays a central role in regulating the viability and activity of neural circuits, thus it is an essential factor in every aspect of healthy brain function. This role is underscored by the wide range of neurological and psychological conditions that are associated with myelin dysfunction and damage. Consequently, the search for molecular targets regulating myelin formation and repair is a key challenge in Neuroscience. A major strategy adopted by the field involves the identification of molecular pathways regulating the differentiation and maturation of oligodendrocytes, the neural cells responsible for generating and repairing myelin in the central nervous system (CNS).

Oligodendrocytes arise from a class of CNS progenitor, termed oligodendrocyte progenitor cells (OPC), that proliferate and migrate widely throughout the developing CNS. Once OPCs reach sites of myelination they begin to wrap target axons and undergo a series of molecular and morphological changes that culminate in the production of a terminally differentiated myelinating oligodendrocyte. These dramatic molecular and morphological changes are mediated, in part, through the actin cytoskeleton, with cell surface receptors, such as leucine-rich repeat and immunoglobulin (Ig)-like domain-1 (LINGO-1), providing a link connecting extrinsic ligands to intracellular actin-regulating pathways (e.g. RhoA/ROCK). to impairments in myelin formation and repair. However, clinical trials of function blocking anti-LINGO-1 molecules failed to reach their primary endpoints, leading to questions around the suitability of LINGO1 as a therapeutic target.

As an alternative to LINGO-1, our group showed that a structurally related molecule, amphoterin-induced open reading frame-3 (AMIGO-3), is present at higher levels in the CNS than LINGO-1, and that it is expressed in myelinating regions of the CNS where it is downregulated prior to the onset of myelination. Our in vitro data identified AMIGO-3 as negative regulator of OPC differentiation, and importantly, it was localised primarily in the plasma membrane, marking it as a likely player in extracellular receptor complex signalling events. Taken together, our data identify AMIGO-3 as a negative regulator of OPC differentiation, and a promising target for therapeutic antibodies designed to promote myelin formation and repair.

This project will study a new AMIGO3 knockout (KO) mouse which we have recently established in Birmingham. The project will examine the hypothesis that AMIGO3 antagonism/knockdown will promote oligodendrocyte differentiation and myelination in vivo. We will document OPC differentiation and myelination in white matter of AMIGO3 KO mice to understand if it is accelerated compared to wild type mice. We will also culture OPC from AMIGO3 KO mice and determine changes in their differentiation compared to wild type littermates.

Because the onset of myelination in normal mouse development typically occurs around postnatal day (P) 5, we will also examine myelination in the brain and spinal cord at ages spanning this age by electron microscopy to further assess if myelination is accelerated in the AMIGO-3 KOs. A major ambition will be to explore the therapeutic potential of AMIGO-3 in myelin disease. Therefore, we explore OPC differentiation and myelin repair in a spinal cord myelin injury model. Here, the myelin toxin lysolecithin (LPC) will be injected into the spinal cord of KO & control mice to create focal demyelination. We will then ask if AMIGO3 KO mice can repair the damage through accelerated OPC differentiation & remyelination.

Additional Funding Information

Project funded by MIBTP’s BBSRC Doctoral Training Programme (https://warwick.ac.uk/fac/cross_fac/mibtp/).

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