JOURNAL CLUB: Differentiation of differentiation differences
David Featherstone
Wednesday, 09 April 2008 21:53 UTC
I grew up in a rural Southern Wisconsin town where pretty much the best stuff to do was drink beer and make fun of people from Illinois. We had no problem with people from Minnesota or Iowa or even Indiana; they’re OK. It was only Illinois people. One time, sitting in the back of a pickup truck at the fair in a thunderstorm, my friends and I saw this woman hustle by. We all immediately agreed that she was from Illinois. How did we know? Well, it was obvious. Illinois people are just different. They do stuff that only Illinois people do. One Thanksgiving, my whole family watched out the window as two guys from Illinois pulled off the road and tried to catch a skunk in a cooler outside my grandma and grandpa’s house. They got the skunk in the cooler and got it all the way to the car. Then suddenly they jumped and waved their arms and dropped the cooler and dived into the car and sped away. The skunk went back to digging for grubs in the front yard. That was funny.
Now, tragically, I actually live in Illinois. When I tell Illinois people that skunk story, they don’t laugh very much. Once in a while, they even ask, “How do you know those guys were from Illinois?” To which I respond: “If they weren’t from Illinois, they wouldn’t have acted like that.” Then I give them the same look I give people who say they don’t like demolition derbies, and punctuate it by reaching into the cooler for another Leinie’s. Once, after telling the skunk story to an Illinois friend, I reached into the cooler and there weren’t any beers left. I was swishing my hand around in the water to make it clear we needed more supplies, but the guy I was drinking with just sat there looking at me unsatisfied. Normally, I wouldn’t spend too much time on the subject with people who obviously don’t know the field, but my mouth was getting pretty dry since finishing the last beer and it was still well before noon, so I decided to go all intellectual: “Well, over decades of study, we Wisconites have identified a number of markers that can be used to reliably distinguish people from Illinois.” He kept sitting there, expectantly, so I continued. “For example, Illinois people drive really fast through town even when they’re sober. And they don’t wear brown corduroy suits for church and holidays like normal people do. Neither of those skunk-catchin’ boys had a brown suit, and they drove pretty fast. That’s two pieces of evidence, right there, in addition to the whole skunk thing.” “Besides,” I added, “me and my family have been telling that story for years, and since the beginning those Illinois boys have always been identified as Illinois boys.” I leaned back and burped, to emphasize the fact that differentiation between Illinois and non-Illinois people was a highly developed science and any questioning of my conclusions was a sign of ignorance. After he had refilled the cooler and we had cracked another couple cans, I even told him the rest of the story. “The funny part is, that car that those Illinois boys stunk up wasn’t even their own. It had Wisconsin plates!”
Questions for discussion:
1) Were those really Wisconsin boys who just happened to drive fast and not wear brown corduroy, meaning that driving fast and lack of brown corduroy are not really reliable markers for Illinois people?
2) Beyond lineage analysis (e.g. Wisconsin people are from Wisconsin, and Illinois people are from Illinois), are there really any reliable categorical differences between Wisconsin and Illinois people?
3) Is the distinction between Illinois and Wisconsin people really useful, or is it an arbitrary distinction, historically rooted?
After you’ve thought about your answers a bit, read the recent paper by Karadottir et al published in this month’s issue of Nature Neuroscience. This paper shows that there are (at least) two types of oligodendrocyte precursor cells in rat P7 cerebellar slices. All OPCs were identified as OPC glia based on the presence of the traditionally ‘OPC glia specific’ markers NG2 & OLIG2, and the absence of a traditionally ‘neuronal-specific’ marker, NeuN. But about half of all OPCs examined had large voltage-gated sodium and potassium currents, fired action potentials, and had glutamatergic and GABAergic synaptic inputs. In other words: There were no obvious electrophysiological differences between neurons and many OPC glia. Depending on your point of view, this news could be either very exciting or deeply disturbing. Either way, the study and the fact that it is published in Nature Neuroscience reveals as much about neuroscientific culture as it does brain function.
Were the ‘OPCs’ studied by Karadottir really neurons that happen to express some ‘glial’ markers? How does one distinguish neurons and glia anyway without relying on markers? If there is no reliable way to categorize a cell as ‘glial’ or ‘neuronal’ without the use of markers, then how can we assign markers as ‘glial’ or ‘neuronal’? Is the continuing functional distinction between ‘glial’ and ‘neuronal’ cell lineages an ultimately disastrous conceptual mistake? If the nervous system is not just neurons (we all know it’s not), and neurons aren’t the only fast electrical signaling, synaptic contact-making cells carrying important information in the nervous system (many studies over the past couple decades have shown that they’re not), then why do we keep calling our field ‘Neuroscience’? Should we simply go back to being ‘physiologists’ or ‘cell biologists’ or ‘behavioral scientists’?
References:
Karadottir, Hamilton, Bakiri, and Attwell, “Spiking and nonspiking classes of oligodendrocyte precursor glia in CNS white matter” Nature Neuroscience 11(4):450-456 [April 2008].
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Replies
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Dear David:
I prefer to call it “Brain Science”.
You pointed to a possible “anomaly” in current cell taxonomy, but this anomaly may be restricted to (relatively) few cells.
The deeper lesson is at the functional level: neurons and astrocytes work together, forming a functional unit: the “synaptic island”, as proposed by Halassa et al. (below).Best
Alfredo
J Neurosci. 2007 Jun 13;27(24):6473-7.
Synaptic islands defined by the territory of a single astrocyte.
Halassa MM, Fellin T, Takano H, Dong JH, Haydon PG.
Silvio Conte Center for Integration at the Tripartite Synapse, Department of
Neuroscience, University of Pennsylvania School of Medicine, Philadelphia,
Pennsylvania 19104, USA.In the mammalian brain, astrocytes modulate neuronal function, in part, by
synchronizing neuronal firing and coordinating synaptic networks. Little,
however, is known about how this is accomplished from a structural standpoint. To
investigate the structural basis of astrocyte-mediated neuronal synchrony and
synaptic coordination, the three-dimensional relationships between cortical
astrocytes and neurons was investigated. Using a transgenic and viral approach to
label astrocytes with enhanced green fluorescent protein, we performed a
three-dimensional reconstruction of astrocytes from tissue sections or live
animals in vivo. We found that cortical astrocytes occupy nonoverlapping
territories similar to those described in the hippocampus. Using
immunofluorescence labeling of neuronal somata, a single astrocyte enwraps on
average four neuronal somata with an upper limit of eight. Single-neuron
dye-fills allowed us to estimate that one astrocyte contacts 300-600 neuronal
dendrites. Together with the recent findings showing that glial Ca2+ signaling is
restricted to individual astrocytes in vivo, and that Ca2+ signaling leads to
gliotransmission, we propose the concept of functional islands of synapses in
which groups of synapses confined within the boundaries of an individual
astrocyte are modulated by the gliotransmitter environment controlled by that
astrocyte. Our description offers a new structurally based conceptual framework
to evaluate functional data involving interactions between neurons and astrocytes
in the mammalian brain. -
When people ask me what I do for a living, I usually say I’m a ‘biologist’, at which point they usually tell me how they always hated biology.
Regarding the paper you cite, Alfredo: That’s an interesting paper, and a great model. Phil Haydon’s lab is one of the biggest proponents of ‘glia do everything neurons do’. But note the undertone of paper: despite the fact that astrocytes make ‘synaptic’ connections, have calcium-dependent transmitter release, and functionally interact with the larger cell signaling network, they still must be relegated to a ‘modulatory’ position. And in any case, astrocytes are only one among a vast array of different types of nervous system cell, all ignominiously lumped together as ‘glia’. Which most people functionally ignore. Isn’t it time we got past the 19th century belief that glia are simply connective tissue? I honestly think the conceptual division of cells between neurons and glia is holding back brain science. It’s time for a revision of nervous system cell taxonomy.
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I think that this paper really challenges the wisdom of hastily defining “non-differentiated” cells. As the authors mention, typical procedure would be to define these cells as destined to ultimately become oligodendrocytes. But it is now clear that half of these cells may not retain the ability to remyelinate axons after injury (or do they?) If they don’t myelinate and reveal active conductances, can they still be oligodendrocytes?
So I agree with Dave that we are learning enough about glial biology to stop considering them as innocent bystanders or stable connective entities, but rather as dynamic, plastic, active contributors to virtually all aspects of brain function and communication.
I attended the Euroglia meeting in London last year and had a fantastic time, learning a lot in the process. With it moving to Paris for 2009, I can only recommend it even more.
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