‘‘Transit amplification in the cerebellum evolved via a heterochronic shift in NeuroD1 expression’’
Posted by Thomas Butts, on 4 August 2014
They are a mouthful, paper titles, sometimes. This is exactly the sort of title that would have made me ignore it in the days when I worked on the evolution of Hox genes. But I now find myself frequently justifying to people who work on evolution why the nervous system deserves attention, and of justifying to neuroscientists why the evolution of their systems is interesting (the latter is harder). Carving out a scientific niche is a very difficult and arduous task at the best of times and requires careful reflection, insight and planning. Above all though, it requires luck. What I have learned thus far about successful scientists though, is not that they make their own luck, as some would have you believe; they don’t. It is that when an interesting observation or finding rears its head, they follow it up. Even if it hadn’t already occurred to them. In fact, especially when it hadn’t already occurred to them. Intellectual flexibility is crucial. Nevertheless, it is apparently good to have a plan so this post is part of my effort to develop one. It is hardly Marx and Engels, but then, I don’t think they had EvoDevo in their day.
So, this post carries the same title as a recent paper that I published with an incredibly talented PhD student, Micha Hanzel, and my former supervisor, Richard Wingate at KCL. I have been invited to write a brief post about it on here by the boss of all things Nodal (ha! Sorry…), Cat Vicente. I normally balk at this kind of shameless self-promotion (sometimes), but I thought that I would indulge in it now for two reasons: to outline why it’s interesting, and to discuss what I mean by the word ‘interesting’. If I stray into the territory of ‘my work is cool because…’ you have my permission to slap me when you next see me.
Our work was on the evolution of development underlying the complex cerebellum found in amniotes. Actually not all amniotes, just birds and mammals. Essentially, they have massive numbers of neurons in the cerebellum and as such a massive cerebellum that is all stereotypically wrinkly in much the same way as the neocortex (the cool bit of the forebrain) of primates. All other groups of vertebrates don’t possess this foliated structure, which has been crucial to amniotes doing all sorts of cool things like manipulating things with their paws/hands, flying, and in primates, thinking. That is not to say that there aren’t a huge variety of interesting cerebellums around the rest of the vertebrate phylogeny – there are – but I was interested in how the amniote one got so impressive*.
Being comparative biologists, we characterised cerebellar development throughout the life cycle of the frog, which like I suspect the tetrapod ancestor had 300 million years ago, has a very simple structure with zero foliation. Now in amniotes, massive amplification of stem cells occurs weirdly on the basal (‘outside’) surface of the cerebellum, the complete opposite of where most progenitors live in the brain (on the inside, next to the ventricle). Given the lack of large numbers of neurons in the frog, we assumed that this external layer would be absent. Early in development it was, but to our surprise, we found the layer much later in development around metamorphosis. However, it was totally non-proliferative. In amniotes the transcription factor NeuroD1 normally acts to cause cell cycle exit and is turned on just as cells leave the external layer; in frog, it was expressed ‘prematurely’ in the external layer.
This led us to try to re-capitulate this condition experimentally in the chick (I had an interview recently where one of the academics said ‘’you chick people, you have it too easy!’’ But it is nice to have experimental manipulation so readily possible). ‘Premature’ NeuroD1 misexpression is indeed capable of causing cell cycle exit and we were able to show, using some funky (well, I think so) combinations of cis regulatory reporter constructs, that it down-regulates the gene Atonal1, which normally facilitates proliferation. Happy days: delaying expression of a single transcription factor enabled the evolution of a stem cell population that drove cerebellum evolution in amniotes.
Now, this is not going to change the world immediately in any predictable way, it won’t solve medulloblastoma (a devastating childhood cancer which develops from the external layer), and it certainly doesn’t address any of the strategic priorities that the grant proposal originally had to be measured against. But it is interesting. Not that it went into Nature or Science, and not that it will revolutionise the way lots of other people do science. It probably (sorry editors/future me) won’t have high ‘impact’. I mean, of course I hope it does, because I am part of this daft system where non-professionals judge my science by the effect it has on the gross domestic product of the UK or some other completely misguided and frankly idiotic metric assessment of an activity that is by its very nature not metrical. I do, though, think it is interesting. Because it explains, in some small way, something about some aspect of the natural world which was previously unexplained. Which is what science is meant to do, isn’t it?
To be clear then, I hope that my work reflects me. It is absolutely and determinedly not ‘cool’. I hate that word. It seems to have replaced ‘interesting’ in the scientific lexicon. It’s nearly as bad as ‘impact’. Why is it that as people, we grow up and stop being slavishly concerned (most of us) about whether other people think we are cool, or copy trends that we set, in our late teens or early 20s, and yet as scientists many of us chase exactly that folly and judge others by it? I don’t care (or rather, I shouldn’t) if no-one copies my experimental or philosophical approach in a way that leads to new insight into the process of root tip growth, the development of circuits implicated in autism, or the dynamics of arthropod leg diversity. They may do, and if so, I will care (and be happy!) about it then. But not now: science is the ultimate unpredictable pursuit. When people pretend otherwise and ‘sales pitch’ their work based on some defined future benefit, they are at best slavishly colluding in a system that is to the ultimate benefit of no one (which at present we all have to do), or at worst downright lying. This work on brain evolution is not ‘cool’ or ‘impactful’ (my all time most hated word), but it is interesting for its own sake and that is all anyone should care about.
*There is enthusiastic controversy surrounding the nature of the cerebellum in fish, and I have partially contributed to this, arguing that it possesses nothing like the same developmental complexity, but I could well be wrong, and so in the interests of civility am giving that topic a wide birth here.
Butts, T., Hanzel, M., & Wingate, R. (2014). Transit amplification in the amniote cerebellum evolved via a heterochronic shift in NeuroD1 expression Development, 141 (14), 2791-2795 DOI: 10.1242/dev.101758
(2 votes)
Loading...
This is so interesting! Opens up a lot of questions (eg. the most obvious ‘What drives NeuroD1 expression in the two species’)
On a side note, it’s news to me (pardon my ignorance), that Atonal has this role in the cerebellum. In Drosophila, Atonal’s only present in the PNS (eye, a specific bunch of sensory organ precursors in other regions…)