The role of serotonin in motor neuron development and regeneration

Motor neurons are the cell type that mediates all movement signals from the brain to the muscles. In neurodegenerative diseases, such as ALS, these cells are lost, leading to paralysis and death of patients. We have previously shown that, in contrast to humans, adult zebrafish can replace lost neurons from stem cells that are present in the spinal cord. Although adult mammals possess these cells, which give rise to motor neurons during development, they apparently to not receive the right signals for motor neuron differentiation at the adult stage. We study the role of the neurotransmitter serotonin in development and regeneration of motor neurons in zebrafish. We found that serotonin stimulates motor neuron development in embryos and we now want to test whether this is also the case during adult regeneration. We will also identify the receptor molecules necessary for the action of serotonin. We have previously shown that signals involved in motor neuron development in zebrafish embryos have similar actions on motor neuron generation from human stem cells. This indicates that results from zebrafish are relevant to the human situation. Thus we aim to elucidate a new signal that could ultimately be harnessed to replace motor neurons in ALS, by differentiating transplantable or endogenous stem cells into motor neurons.

In contrast to mammals, adult zebrafish are capable of regenerating motor neurons after a lesion of the spinal cord. We are investigating the signals that make adult progenitor cells revert to a motor neuron generating stage. In a recent drug screen for signals that enhance motor neuron development we found that serotonergic drugs and serotonin markedly increase the number of HB9:GFP positive motor neurons in embryonic zebrafish. Since developmental signals are likely recapitulated during adult regeneration, we hypothesise here that serotonin plays a role in motor neuron development and adult regeneration. Using in situ hybridisation, pharmacological profiling and morpholino-mediated gene knock down we will characterize the specific serotonin receptor(s) involved in the response to serotonin. Microarray analysis will elucidate down-stream gene regulation of serotonin signalling, Finally, we will pharmacologically perturb motor neuron regeneration in adult lesioned fish. Translatability of zebrafish results is high. For example, we have recently shown that dopamine, found to augment motor neuron development in zebrafish also enhances motor neuron differentiation in human embryonic stem cell cultures. Thus identifying signals for motor neuron differentiation in zebrafish can directly inform stem cell research. This may ultimately lead to stem cell therapies of devastating motor neuron degenerative diseases, such as ALS.

Communications and Engagement CNR sponsors an exciting internal and external lecture series that includes Brain Awareness Week, Edinburgh Neuroscience Day, and the Annual Distinguished Lecture. Brain Awareness Week presentations are completely open to the public. The School of Biomedical Sciences also provide 'Briefings', summaries of the research findings of each Principal Investigator written for a lay audience, on its website. I was a speaker at the Edinburgh Neuroscience Day 2008. Work from my laboratory has been the topic of a university press release in April 2009, for which I closely worked with the University's press officer, Ms Tara Womersley. This led to National media coverage (BBC website and BBC radio, Herald, Telegraph, The Metro and others). Most recently, our work has been covered in the University 'Friends' magazine in January 2010 and the Packard Center's ALS-Alerts Spring 2009 and Summer 2010 (after consultations with their press officer, Mrs Marjorie Centofanti). Furthermore, the Euan MacDonald Centre and MND Scotland have organised opportunities for their scientists to engage with patients, their relatives and other interested parties, including potential donors, which I also attend (for example the 'Bash at the Brewery' in June 2009, MND Scotland Open Day in May 2010). Developmental Biology is a particularly attractive topic to engage pupils in science. We have run workshops for primary school pupils at a local school in their 'Science Career Fair' and science lessons. We plan to continue our engagement at this and other schools. Collaboration We are working together with 'Edinburgh Research and Innovation' (ERI), the commercialisation branch of the University, to evaluate the commercial value of our research. For efficient communications of our findings, we collaborate with the University press office and public relations officers of the Euan MacDonald Centre for Motor Neurone Disease Research (Edinburgh) and the Robert Packard Center for ALS Research at Johns Hopkins of which we are members. Exploitation and Application The current proposal is basic research, but may ultimately inform therapeutic approaches and therefore could, in the long term, yield commercially exploitable results. Research programmes at the CNR benefit from close interaction with 'Edinburgh Research and Innovation' (ERI), the commercial branch of the University, which ensures early identification of commercial potential and support for any patent application or translation. In early 2008, we developed a new method for a multi-stage drug screening method, which, after consultation with ERI's Head of Research and Business Development, Dr Michael Finnen, was filed for patent in the UK on 1. July 2008 and for PCT on 1. July 2009 and has received very favourable reviews. The submission costs were provided by the University after internal review. We will liaise with Dr. Finnen in regular intervals to assess any commercial potential of our studies. I am interested in developing industry contacts and have given a presentation on our research at Astra Zeneca's Gothenburg site in November 2009. Capability Many impact activities, described above, have been performed by me or the Co-PI of the group, Dr. Thomas Becker. Our current post-graduate students current PhD and MSc students Ms Norris, Ms Zhong, Mr Wyatt and Ms Dias have led 'Build a Brain' and 'Science Festival' activities at the local National Museum of Scotland and Ms Dias has gone through training by MND Scotland to present scientific findings to the public. Ms Norris is on the editorial team of the Edinburgh student newspaper EUSci. Furthermore, Ms Zhong is a co-organiser of a Roberts Fund funded post-graduate careers seminar, which is entirely student-led and invites speakers from all areas of possible career paths for science PhDs (e.g. industry, media, academia). There are no cost implications for the BBSRC from these activities.