At University College London’s Schwann cell Research Department of Cell and Developmental P

myelination RO Biology, great progress F has been made in ESSORS To provide some background, what role it is globally regulated by the transcription understanding the role do Schwann cells play in the nervous factor c-Jun, which on nerve injury activates

system, and what has inspired your two cellular programmes in Schwann cells, a K that Schwann cells play in interest in these cells? dedifferentiation and a repair programme. In RISTJAN allowing regeneration of this way c-Jun directs the transformation of Let us start by putting Schwann cells in normal adult Schwann cells to a novel Schwann

injured nerves. Professors R

context. It sometimes feels like the best kept cell variant that is dedicated to support Kristjan R Jessen and secret in neuroscience that the nervous system regeneration. We aim to understand how JESSEN (brain, spinal cord and peripheral nerves) is c-Jun controls the biology of this dedicated

Rhona Mirsky explain only partly made up of nerve cells. The majority repair cell, how it interacts with other signals, AND how a novel approach has of nervous system cells are, in fact, glial cells, including Notch and signals shown by other

which have quite distinct biological properties workers to be involved in Schwann cell injury, R and function from nerve cells. and how we can manipulate these factors to H highlighted the importance ONA of these cells boost the repair programme to improve the As with neurons, there are different types of success of nerve repair, an issue of significant M

glial cells. Schwann cells, the cell type we work clinical importance. IRS

on, is the main glial cell in peripheral nerves. KY These cells envelop all nerve fibres and are Why is it that the molecular mechanisms required for nerve development and function. that control the Schwann cell injury But the aspect of these cells that we are excited response have been poorly understood? about now is their role in nerve pathology. In particular, we are focused on the intriguing In retrospect, we can perhaps see that a main dichotomy that while the glial cells of the reason was the inadequacy of one of the brain respond to injury by suppressing repair, dominant ideas for describing the process. Schwann cells respond in the opposite way by This viewed the injury response essentially as promoting repair and functional recovery. dedifferentation or reversal of myelination, which is the last step of Schwann cell What are the interlocking issues in Schwann differentiation. According to this hypothesis, cell biology that have been addressed by the injury response represents a passive your research group? return to a default state, caused by injury- induced removal of signals that maintain Earlier work by our group centred on Schwann differentiation/myelination. Within this cell development. This involved a detailed framework there was little point in looking for molecular characterisation of known cell novel signals that actively drive the process. stages and led to the identification of a new This perspective changed when we realised cell type – the Schwann cell precursor – that that the injury response is better described provided the missing developmental link as a double act – dedifferentiation coupled between the neural crest and Schwann cells. to activation of an alternative differentiation This, in turn, motivated the identification pathway specialised for repair, leading to a of signals that control these transitions and change in cellular function, a process that cell types. Importantly we also identified has much in common with processes called molecules, namely c-Jun and Notch that transdifferentiation in other systems. acted to inhibit the last critical step in Schwann cell development – the formation What would you say has been your most of an insulating sheath, myelin, around nerve significant finding to date? fibres. This finding formed the basis for our current research on nerve repair. The identification of the Schwann cell precursor made it possible to conceive a Can you give an outline of the research comprehensive outline of Schwann cell currently conducted in your laboratory? development, and this finding has led to numerous studies by other groups. Another Damage to peripheral nerves triggers a significant finding is that repair in the striking transformation of the Schwann cells peripheral nervous system depends on the at and beyond the injury site, the Schwann activation of c-Jun in injured Schwann cells, cell injury response. This enables peripheral and that c-Jun works by globally regulating nerve fibres to regrow and restore function, the transdifferentiation of Schwann cells into in contrast to what is seen in the brain and dedicated repair cells. This may throw new spinal cord, where injury results in permanent light on the repair-inhibitory response of brain disability. Our objective is to understand this glial cells to injury, and hopefully result in important response. We have found that novel ways to improve peripheral nerve repair.

WWW.RESEARCHMEDIA.EU 121 PROFESSORS KRISTJAN R JESSEN AND RHONA MIRSKY Exploring the peripheral nervous system An important study of Schwann cell myelination and response to nerve damage is unlocking key mechanisms relevant to nerve repair and pathology; mechanisms which could lead to new therapeutic targets for patients suffering from nerve injury or neuromuscular genetic disease

AFTER INJURY, NERVE fibres of the peripheral organisers of nerve repair. In contrast, the closely nervous system (PNS) have a remarkable ability to related glial cells of the central nervous system regenerate, leading to recovery of normal function. (CNS) actively prevent axon growth and recovery This process is governed by glial cells known as following injury. Schwann cells and by their unusual capacity to metamorphose into a cell that drives the healing The remarkable plasticity of Schwann cells, and process. In uninjured nerves, the Schwann cells their ability to switch between differentiation are either non-myelinating or myelinating, states, is unparalleled in most other mammalian the latter cells forming myelin sheaths around systems, and if manipulated could lead to axons, which allow fast conduction of nerve improved nervous system repair and treatment impulses. In damaged nerves, however, Schwann for those suffering from neuropathies. cells transform their molecular properties and morphology and switch function to that of SCHWANN CELL PRECURSOR ensuring repair. These cells support the survival of injured neurons, stimulate nerve fibre growth To analyse the processes that govern Schwann and deal with breakdown of myelin that otherwise cell plasticity and to understand how this would hinder regeneration. They also form enables the regeneration of peripheral nerves, regeneration tracks, called Bands of Bungner, that Professors Kristjan R Jessen and Rhona Mirsky guide nerve fibres back to appropriate destinations of the Department of Cell and Developmental so that function can be restored. Schwann cells in Biology at University College London, UK injured nerves, Bungner cells, are therefore central began by identifying the steps involved in the development of Schwann cells: “We sought to define cellular transitions and intermediary cell types that are required for a developing nerve to build adult Schwann cells from a transient stem cell population, the neural crest that is found in the mid-term embryo,” they reveal.

As a result of these studies, Jessen and Mirsky were the first to identify the Schwann cell precursor. This cell type, which arises from the neural crest, goes on to form immature Schwann cells which then differentiate into myelin and non-myelin (Remak) adult Schwann cells. Building upon this clearer understanding of cellular transitions, Jessen and Mirsky were able to determine and investigate signals involved in controlling the transitions, including Neuregulin, transforming growth factor (TGF ), Notch and Desert hedgehog (Dhh).

More recently, Jessen and Mirsky have adopted a fresh approach to study the Schwann cell FIGURE 1. Electron micrographs showing nor- response to nerve injury, which has led to some mal and dysfunctional regeneration tracks in exciting findings. It was known that the Bungner peripheral nerves, distal to an injury. The upper cells generated after injury are dedifferentiated, picture shows two normal regeneration tracks losing the myelin sheaths and other features (one is arrowed). Each track is composed relevant to Schwann cell function in undisturbed of a number of narrow, elongated Bungner nerves. Jessen and Mirsky realised, however, Schwann cells shown here in a transverse that perhaps of even greater significance, these section. The lower picture shows a comparable cells also gain a number of other features that area from an injured nerve of a mouse without specifically promote repair. Therefore, the c-Jun in Schwann cells. Classical regeneration injury response taken as a whole represents tracks do not form and the Schwann cells are reprogramming and a change of function, a irregular and flattened. WT: normal mice; cKO: process that resembles transdifferentiation which mutant mice in which c-Jun in Schwann cells is well-described in other biological systems. On has been inactivated. Bar: 1 µm. this basis, Jessen and Mirsky began a search for signals that control this important phenotypic 122 INTERNATIONAL INNOVATION C!JUN ACTS AS A INTELLIGENCE GLOBAL REGULATOR MECHANISMS OF SCHWANN CELL MYELINATION AND Jessen and Mirsky DEDIFFERENTIATION: RELEVANCE TO have also unveiled the NERVE REPAIR AND PATHOLOGY important role that c-Jun plays in gene OBJECTIVES expression in Schwann cells. Interestingly, this Unlike the brain and spinal cord, peripheral function of c-Jun appears nerves regenerate when injured. This is because the nerve glial (Schwann) cells restricted to injury have a striking capacity to transform to a and other pathological cell specialised for supporting repair. Two conditions such as Schwann cell factors – c-Jun and Notch – genetic demyelinating control this transformation and have major diseases. Uninjured impacts on neuronal injury responses. The nerves of mutant aim is to understand how these factors work mice were found to be and to manipulate them to improve the FIGURE 2. The main cell types and developmental and injury-induced transitions physiologically normal, outcome of nervous system injury. in the Schwann cell lineage. Black uninterrupted arrows: normal development. Red and comprehensive arrows: the Schwann cell injury response, resulting in the formation of the Bungner analysis of gene KEY COLLABORATORS expression revealed repair cell. Stippled arrows: post-repair reformation of myelin and Remak cells. Dr Axel Behrens, Cancer Research UK • Dr only two differentially Lawrence Wrabetz; Dr Laura Feltri, Hunter expressed genes. c-Jun James Kelly Research Institute, University switch: “This alternative hypothesis immediately does therefore not appear to have a significant at Buffalo, New York, USA • Professor raised new and, as it has turned out, fruitful role during the normal function of Schwann cells Gennadij Raivich, University College questions about how the repair programme or in Schwann cell development. London, UK • Dr David Parkinson, Peninsula is activated, how the dedifferentiation and Medical School, Plymouth, UK • Dr Dies redifferentiation programmes are coupled and In contrast, the Bungner cells generated after Meijer, Erasmus University, Rotterdam, whether we can identify pathways that amplify injury were strikingly dysfunctional. Analysis of The Netherlands the repair programme to promote repair”. gene expression in the injured nerve stumps of mutant and control mice revealed 172 significant FUNDING differences. A wide range of molecules that have C!JUN AND SCHWANN Wellcome Trust been reported to influence neuronal regeneration CELL INJURY RESPONSE were abnormally expressed, including growth Medical Research Council A key signal that appeared to determine the factors such as GDNF, artemin and BDNF, EU Seventh Framework Programme (FP7) Schwann cell injury response was the transcription growth-associated proteins, cell surface adhesion factor c-Jun, highly expressed in Schwann cells of molecules, as well as other transcription factors. CONTACT cut nerves. Initially, Jessen and Mirsky found that Through these studies, Jessen and Mirsky have mutant mice with conditional deletion of Schwann revealed that c-Jun controls the molecular Professor Kristjan R Jessen, PhD, FMedSci cell c-Jun showed a delayed loss of myelin proteins reprogramming involved in the transformation Professor of Developmental Neurobiology and mRNA in response to nerve transection. of mature Schwann cells into the Bunger cells Research Department of Cell and Because c-Jun in this way took part in controlling generated after injury. This finding has allowed Developmental Biology the Schwann cell response, and because Schwann them to conclude that c-Jun acts as a ‘global University College London cells in turn are potent regulators of nerve cells, regulator’ of the Schwann cell repair programme Gower Street this raised the question of whether Schwann cell that drives regeneration of injured nerves. This London, WC1E 6BT, UK c-Jun also controlled the way nerve cells reacted realisation could lead to better strategies for when peripheral nerves were damaged. repair after accidental injury to peripheral nerves. T +44 20 7679 3351 E [email protected] To address this, their laboratory first looked at NEUROPATHY TREATMENT www.ucl.ac.uk/jessenmirsky the relative levels of neuronal death in mutant mice without Schwann cell c-Jun and control Identification and increased understanding PROFESSOR KRISTJAN R JESSEN obtained mice. They found that, following nerve injury, of the role of Schwann cell c-Jun could also MSc and PhD degrees in Neuroscience the mutant mice showed substantially higher prove important in the quest for treatment of at University College London (UCL). He levels of neuronal death. For example, following demyelinating or axonal neuropathies affecting has been Professor of Developmental injury, small, unmyelinated dorsal root ganglia the myelin sheath and axon, respectively. The Neurobiology in the Research Department (DRG) sensory neurons were approximately most common inherited neuropathy is Charcot- of Cell and Developmental Biology, UCL twice as likely to die when Schwann cell c-Jun Marie-Tooth disease (CMT). This disease can be since 1993. Jessen became a Fellow of the was absent. Importantly, about a third of the demyelinating or axonal and is characterised by Academy of Medical Sciences in 2002. large myelinated DRG neurons died in the progressive loss of muscle tissue, touch sensation injured mutants, although these neurons are and motor function. There is currently no known PROFESSOR RHONA MIRSKY obtained her highly resistant to damage, both in control mice cure for CMT and treatment options are limited. PhD degree in Chemistry from the University and in other species. of Cambridge. She has been Professor of Together with colleagues, Jessen and Mirsky are Neurobiology in the Research Department They also found that Schwann cell c-Jun controlled currently investigating the presence of c-Jun in of Cell and Developmental Biology, UCL the rate of axonal regeneration, both in vivo and the Schwann cell nuclei of pathological nerves. since 1990. Mirsky became a Fellow of the in cell culture models of nerve repair, and that Preliminary results indicate that c-Jun is absent Academy of Medical Sciences in 1999. this protein was key to the functional recovery of in intact, normal nerves yet present in diseased/ nerves following injury. When sensory and motor dysfunctional nerves. Future studies should shed function in the mutant mice was measured, further light on these findings and determine minimal functional recovery was reported even whether c-Jun plays a positive or detrimental after 70 days, whereas in control mice, function role. This in turn could inform the search for new was restored after 3-4 weeks. therapeutic targets. WWW.RESEARCHMEDIA.EU 123