Vive la difference!

It could be easy to assume that one motor neurone is pretty much like another, but a series of presentations on Thursday clearly showed that we need to be a little more sophisticated in our thinking.

Dr Hynek Wichterle (Columbia University) discussed how in the developing embryo, there are distinct regional subtypes of motor neurones in the spinal cord. For example, the motor neurones at the bottom of the spine can be easily distinguished from those at the top of the spine by the pattern of genes that are switched on and off – in a nutshell, different motor neurones have their own regional ‘postcode’.

Dr Wichterle went on to show that you can generate motor neurones with specific postcodes  in the lab, from embryonic stem cells . Having motor neurones  that  hopefully reflect different aspects of MND will allow researchers to better understand the subtleties of motor neurone function and develop more relevant treatment approaches.

It’s well known that some motor neurones are particularly resistant to the disease, such as the so called ‘oculomotor neurones’ that control eye movements. By looking at  the pattern of genes  being switched on and off in early mouse embryonic development, Dr Wichterle was able to induce the same pattern in mouse stem cells to create what look very much like oculomotor neurones in the dish. There is some further work to be done to check that they are indeed what he thinks they are, but they could be a very important tool in helping to understand why some motor neurones are tougher than others.

Continuing the theme, Dr Georg Haase  (Marseille) introduced an elegant way of separating different populations of motor neurones from mouse spinal cord. He focused on two subtypes of motor neurone – those that connect to the limb muscles  and those that connect to the main trunk of the body. After they are separated out, they can be grown in culture (in a dish in the lab) . He then showed that these two different subtypes of motor neurone acted very differently in their response to chemicals known as neurotrophic factors . The word neurotrophic can be literally translated as ‘nerve nourishing’ and these chemical compounds have attracted a lot of attention in the past as possible therapies for MND, with a couple being tested in large clinical trials . Unfortunately these trials have not shown any effect, but this could be because  – as Dr Haase showed in his lab studies – each neurotrophic factor only acts on a proportion of motor neurones. He suggested that the different ‘survival profiles’ he sees in his cellular studies  provide a rationale for selecting combinations of different neurotrophic factors for further testing in mice – and hopefully in man.

Prof Pam Shaw (University of Sheffield) also asked the question of what makes  oculomotor neurones  different, but her presentation took us from mouse to man. Using a technique called laser capture microdissection, which allows individual motor neurones to be removed from post mortem spinal cord tissue form MND patients, she and her colleagues are able to examine which genes  were switched on and off in the cells. Research like this requires very high quality tissue, removed shortly after death, but Sheffield happens to host one of the best MND tissue banks in the country.

She compared these ‘gene expression patterns’ in the disease-resistant oculomotor neurones with the more vulnerable motor neurones  from the lower spinal cord. There were  considerable differences in the patterns, with a much larger number of genes being switched on in the oculomotor neruones. Many of these genes could be dividied into functional families, which act on a similar biological pathway. Key protective processes activated included neurotransmission, mitochondrial function and proteasomal function – all of which are strongly implicated in MND. If human oculomotor neurones  survive by gearing up these  protective pathways, it provides possibilities that drugs can be found which act in the same way.

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Stem cell conference part two: How are motor neurones created from stem cells?

Creating motor neurones for research is a lengthy and expensive process, so Prof Kevin Eggan from Harvard University  Massachusetts, asked whether we can predict at an early stage which stem cell lines will be the most useful in generating the best quantities of motor neurones, saving time, effort and money. He has been developing a ‘scorecard’ which he believes will help work out which cell lines are most useful.

But if you make motor neurones from skin cells, are they really motor neurones? At the moment there is no consensus on what makes a neurone a motor neurone, so Prof Eggan outlined a series of tests used in his lab that “provide confidence that these have more than a passing resemblance to motor neurones”. Additional encouraging results suggest that motor neurones created from ‘adult’ iPS cells are “pretty indistinguishable from those obtained from embryonic stem cells”. There are some differences, so comparative work using both types will need to continue for the forseeable future.

Prof Siddharthan Chandran, MND Association funded researcher at Edinburgh University then posed the question: “Do they reflect the different types of motor neurone found in the human body? There is no such thing as a ‘generic’ motor neurone, each one has its own postcode.”

So, can stem cell-derived motor neurones reflect the diversity of subtypes found in the human body? For example, the motor neurones that control eye movement are much more resistant to the disease than other motor neurone types, and motor neurone controlling limb muscles can behave differently from those controlling the trunk muscles.

The answer is preliminary, but encouraging.

Prof Hynek Wichterle, from the Columbia University New York, presented research showing that embryonic stem cells can be turned into different subtypes of motor neurone and Prof Chandran has been working on the same issue using iPS cells.

There is a lot of work to do, but having human motor neurones in a dish that faithfully reflect the diversity of types found in the body will greatly assist understanding of MND and may also help in identifying potential drugs that might target highly vulnerable motor neurone populations in patients with different clinical patterns of disease.