Patterning the nervous system with Bmp

I'm a little surprised at the convergence of interest in this news report of a conserved mechanism of organizing the nervous system—I've gotten a half-dozen requests to explain what it all means. Is there a rising consciousness about evo-devo issues? What's caused the sudden focus on this one paper?

It doesn't really matter, I suppose. It's an interesting observation about how both arthropods and vertebrates seem to partition regions along the dorso-ventral axis of the nervous system using exactly the same set of molecules, a remarkable degree of similarity that supports the idea of a common origin. Gradients of a molecule called Bmp may be the primitive mechanism for establishing dorso-ventral polarity in animals.

The way the article is phrased, it sets up the results as "contrary to the prevailing view," which is sort of true, and sort of not. It's a novel result that provokes some interesting ideas about animal ancestors, but I also think that views on this matter are in quite a bit of flux…so going contrary to any prevailing view doesn't represent too great a shake-up. Some of the confusion about the importance of the work arises, I think, because there two waves of dorso-ventral specification to consider. Early in development, the dorsal and ventral sides of the embryos of different phyla are established in a similar manner. One side of the embryo expresses a signalling molecule called Bmp (bone morphogenetic protein) in vertebrates or Dpp (decapentaplegic) in Drosophila; the other side expresses Chordin (the homolog in invertebrates is sog, short gastrulation). Bmp suppresses nervous system development, while Chordin permits it, so the side without Bmp forms the nerve cord. The similarities in whole body patterning of both vertebrates and arthropods have been well established.

(In vertebrates, the Bmp side is the ventral side, while in invertebrates, the Bmp side is the dorsal side; we have a dorsal nerve cord, they have a ventral neural plate. We're inverted relative to each other, but don't let that confuse you—we're using the same molecular mechanisms to define the dorsal-ventral axis. I have more discussion of this pattern in hemichordates.)

Later in development, in vertebrates, the neural tube forms from the dorsal sheet of neurectoderm. It rolls up into a tube and comes to lie inside the animal. This is where it gets interesting: the neural tube, which arose from a region where Bmp is low, now expresses Bmp dorsally. Ventrally, it expresses another signalling gene, Shh (sonic hedgehog). Basically, it's re-expressing two competing gradients of molecules, but now within just the neural tube. In the diagram below, Bmp is active in the roofplate (in blue), while Shh (in red) is active in the floorplate, establishing a double gradient.


This double gradient is important: it establishes positional information in the dorsoventral axis of the neural tube that is read by the cells within it, and used to determine identity. Ventrally, for instance, cells where Bmp is low and Shh is high will differentiate into motoneurons, while dorsal cells where Bmp is high and Shh is low will become specific classes of interneurons. These competing gradients are what establishes the layered organization of the spinal cord.


Now that is the situation in vertebrates. What about invertebrates? Do they do the same thing, and re-establish a Bmp gradient in their nervous system that patterns the tissue? That has been a difficult process to assess, because of a difference in the organization of the nervous system. In the diagram below, the vertebrate is on the right, and the neural tube has formed as a separate tube of cells within the animal, and is isolated from the body wall (in gray). It's expressing some key genes—Msx, Gsh, Nkx2.1—in a layered fashion. In Drosophila, on the left, the neural sheet is also expressing homologous genes in a similarly patterned sequence, but notice that it hasn't rolled inward. It's contiguous and continuous with the gray body wall, and basically just forms the insect's ventral floor.


This arrangement makes it difficult to assess whether Bmp is playing a role in patterning the expression of neural tissue. Why? Because there are other genes involved in more general D/V patterning of the whole body that are expressed coincidentally with Bmp/Dpp. In particular, there is a gradient of nuclear localization of a gene called dorsal that is a major regulator of dorso-ventral identity everywhere in the animal; how can we separate the effects of the dorsal gene and the Bmp/Dpp gene?

The work of Mizutani et al. gets clever here. They're asking whether the network of genes that define subsets of neurons in the insect are like the network in vertebrates, so what they need to do is remove the confounding expression of the other D/V genes. To do this, they create hopelessly doomed embryos that have the early D/V signals set to uniform levels. The dorsal gene is uniformly localized everywhere, so that every cell in the ectoderm thinks it should make neural tissue, turning the whole embyo into a uniform tube of neurectoderm. Then, they couple the expression of Bmp to a promoter for stripe 2 of the even-skipped gene: this creates a band of Bmp anteriorly, and a gradient of Bmp that runs longitudinally.

This embryo is totally screwed! It is not going to survive, and the various signals for neural development are all running in the wrong directions. The embryo is really just a simplified testbed for determining how neural cells will respond to the Bmp gradient—even more basically, do they respond to a Bmp gradient at all?

You can look at the paper yourself; it's on PLoS biology, which means that everyone can read it online (isn't that wonderful?) What you'll see in the data section is beautiful color photos of fly embryos that look like easter eggs, where colored markers tag patterns of expression of various genes associated with particular neural types. The key result, though, is that there are bands of differing activity in response to a Bmp gradient, exactly as we see in vertebrates!

Here's their summary diagram, illustrating that homologous genes with similar patterns of interactions are expressed in both the Drosophila neurectoderm and the vertebrate neural plate. Similar genes, similar rules, similar patterns: it sure looks like a conserved evolutionary pathway to specify neural identities.

Simplified summary model indicating the proposed similarities in BMP-mediated patterning of the vertebrate and invertebrate neuroectoderm. Two processes collaborate to establish the pattern of neural identity gene expression in Drosophila and vertebrates: graded BMP signaling preferentially represses expression of ventral neural identity genes (left), which then engage in a chain of ventral-dominant repression wherein more ventral genes prevail in repressing the expression of more dorsal genes (right). The indicated inhibition of Msx1/2 by Pax6 remains hypothetical. Not indicated on this scheme are additional levels of cross-inhibition (e.g., Vnd inhibition of msh, late Ind repression of vnd, and Pax6 repression of Nkx2.2), which are likely to help sharpen and refine the pattern created by the core mechanism of threshold-dependent BMP repression coupled to ventral dominance.

The high degree of correspondence in the neural specification pathways of flies and vertebrates strongly suggests that this is a reflection of a conserved function, that the last common ancestor of both phyla used this mechanism to pattern its nervous system. Other components of the patterning mechanisms, like the dorsal gene and Shh, seem to be late additions that are unique to specific lineages, so the suggestion is that the Bmps are the primitive D/V patterning molecules.

Just to throw a spanner into the works, though, here's a problem: the hemichordates. In my previous article and in another paper in PLoS Biology, the hemichordates are described as a sister phylum to the chordates: they are deuterostomes, and thus more closely related to us than to the arthropods. The complication is that they don't have much of a nervous system at all, but instead have a distributed array of nerve cells that aren't localized. Lowe et al. interpret this to mean that the last common ancestor of chordates and hemichordates, and of arthropods, didn't have a neural tube to pattern!

There are a couple of different ways to resolve these interpretations.

  • To fit Mizutani et al.'s explanation, the last common ancestor had a discrete nervous system that was patterned with a Bmp gradient, and the hemichordates secondarily lost theirs. The hemichordate condition is derived.
  • To fit Lowe et al.'s ideas, the last common ancestor lacked a nervous system, and chordates and arthropods independently evolved them; both co-opted an existing molecular pathway, the Bmp system, to do the same thing. In this case, the patterning system of the nervous system is convergent. The Bmp system could still be the primitive D/V patterning molecules for the whole organism, it has just been independently reused in the CNS of both phyla.

The way to resolve this is, of course, more comparative data. How are the Bmps used in the Lophotrochozoa? How about urochordates and echinoderms (not that the latter have much of a nervous system to pattern)? Are there developmental modules like the Dpp/vnd/ind/msh pathway present in animals that lack distinct nervous systems? Whatever the answer is, it looks like it will be fun to figure out.

Lowe CJ, Terasaki M, Wu M, Freeman RM, Runft L, Kwan K, Haig S, Aronowicz J, Lander E, Gruber C, Smith M, Kirschner M, Gerhart J (2006) Dorsoventral Patterning in Hemichordates: Insights into Early Chordate Evolution. PLoS Biology 4(9):e291.

Mizutani CM, Meyer N, Roelink H, Bier E (2006) Threshold-Dependent BMP-Mediated Repression: A Model for a Conserved Mechanism That Patterns the Neuroectoderm. PLoS Biology 4(10): e313.

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I still need to read the papers, so my comment may be completely irrelevant to them. What really amazes me is the amount of complexity the ur-bilaterian seems to have had. I am somewhat predisposed to accept Mizutani et al's explanation (although I might warm to the alternative, after reading the actual studies). It is things like the conserved role of Distalless in appendage development from flies to humans that push me to this view. To hell with Haeckel's embryos - this stuff is far more pursuasive.

To clarify, do hemichordates have bmp-dependent patterning of any kind?

PZ, you seem to be the best person I know to ask this and this thread seems somewhat relevant. While reading Dawkins' The Ancestor's Tale I came across the idea that the first deuterostomes were protostomes that "turned over on their backs", and so reversed their dorsoventral axis. Although Dawkins tries to be as fair and objective as possible he does seem to have a tendency to very occasionally misrepresent his favourite hypotheses as the scientific concensus. How much support has this idea had recently?

Follow the link to the Lowe article, or read my summary -- yes, hemichordates have Bmps, and they use them for D/V patterning.

The idea that there was an inversion between chordates and arthropods (and that chordates are probably the derived form) is pretty much the consensus. John Gerhart wrote an interesting speculative review about alternatives to that model, but I didn't find the alternatives too persuasive, simply because they weren't parsimonious. They involved things like multiple nerve cords and differential loss, or different patterns of migration and coalescence of primordia. Basically, there are other possibilities, but none as simple as an ancestor with a fairly indeterminate top/bottom, with one lineage committing to one side as dorsal, the other making that side ventral.

In re the apparent paradox with the hemichordates:

OMG, OMG, it has to have been an intelligent designer. Michael Behe is right! The edifice of evolution is crumbling! Suddenly I find myself wondering why there are PYGMIES+DWARFS!?!?!?! Nooo!!!!!!!!

Etc, etc.

Actually, I'm really kind of excited to see how the hemichordate thing turns out. That's such a neat puzzle.

By Anne Nonymous (not verified) on 12 Sep 2006 #permalink

Thank you, Professor Myers, for the fascinating intellectual excercise.
Out of curiosity, which theory do you perfer yourself about the hemichordate question? Actually, Dawkins points out how many times(about 30, I think)the eye was invented independently, and so the second theory is plausible, but I personally prefer Mizutani's idea.
By the way, where is Jason when we need him? It would be nice to see what he has to say HERE.

By mndarwinist (not verified) on 12 Sep 2006 #permalink

My bias (and that is all it is, I will be easily swayed by the evidence) is based on two things.

1. Brains aren't everything, most organisms need minimal intelligence, and it ought to be fairly common in evolution for animals to ditch the expensive fripperies; and

2. the diverse developmental pathways are a rich reservoir of molecular tools ripe for co-option, and I can imagine that developmental complexity could have been spawned by a functional complexity in the nervous system.

So I kind of lean towards the presence of a nerve cord in that ancestral bilaterian that was secondarily lost in some lineages. Kinda. I won't weep if the other hypothesis wins out.

There are a range of hybrid possibilities between those two. There could have been an ur-bilaterian with something neural-tube like, but relatively unpatterned along the DV axis or patterned by another mecahnism. This structure is lost or cryptic in hemichordates, while arthropods and chordates both hit on BMPs, which of course have been co-opted for a LOT of different types of developmental signaling. There really are only so many morphogens to choose from, and each pathway has functional properties that might make it uniquely suited to certain situations.

Ouch! There is a range....

I'm a little surprised by...

Why should you be surprised? Look at your blog stats and the number of people who link to you. You are becoming, if you are not already, one of the most trusted and respected science popularizers on the Net.

Thanks, from a member of your extended classroom.

By speedwell (not verified) on 13 Sep 2006 #permalink

Seconding speedwell:

My undergraduate concentrations were in molecular and developmental biology and biomedical ethics. While I now work as an actuary, this site is right at the top of my list of must-reads for continuing self-education. Keep up the good work Professor!

Echoing Speedwell:

Although I left the rigors of science early for the warm gooey creative space that the language arts afforded me, I never lost interest in the way things work and what processes we use to figure out the most plausible explanation of the evidence.

I was never that interested in the 'tiny bits' of biology until I wound up here looking for info on the Dover trial. Your eloquence and tone hooked my interest like a dozen toothed suckers and made me interested in science again.

Me three! As an economist with two measly undergrad biology courses behind me I find your illustrations of the importance of comparative genetics to piecing together development and function website endlessly fascinating and informative. A real public service.