Ancient rules for Bilaterian development

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Assuming that none of my readers are perfectly spherical, you all possess notable asymmetries—your top half is different from your bottom half, and your front or ventral half is different from you back or dorsal half. You left and right halves are probably superficially somewhat similar, but internally your organs are arranged in lopsided ways. Even so, the asymmetries are relatively specific: you aren’t quite like that Volvox to the right, a ball of cells with specializations scattered randomly within. People predictably have heads on top, eyes in front, arms and legs in useful locations. This is a key feature of development, one so familiar that we take it for granted.

I’d go so far as to suggest that one of the most important events in our evolutionary history was the basic one of taking a symmetrical ball of cells and imposing on it a coordinate system, creating positional information that allowed cells to have specific identities in particular places in the embryo. When the first multicellular colony of identical cells set aside a particular patch of cells to carry out a particular function, say putting one small subset in charge of reproduction, that asymmetry became an anchor point for establishing polarity. If cells could then determine how far away they were from that primitive gonad, evolution could start shaping function by position—maybe cells far away from the gonad could be dedicated to feeding, cells in between to transport, etc., and a specialized multicellular organism could emerge. Those patterns are determined by interactions between genes, and we can try to unravel the evolutionary history of asymmetry with comparative studies of regulatory molecules in early development.

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Coming to Life

Books from Nobel laureates in molecular biology have a tradition of being surprising. James Watson(amzn/b&n/abe/pwll) was catty, gossipy, and amusingly egotistical; Francis Crick(amzn/b&n/abe/pwll) went haring off in all kinds of interesting directions, like a true polymath; and Kary Mullis(amzn/b&n/abe/pwll) was just plain nuts. When I heard that Christiane Nüsslein-Volhard was coming out with a book, my interest and curiousity were definitely piqued. The work by Nüsslein-Volhard and Wieschaus has shaped my entire discipline, so I was eagerly anticipating what her new book, Coming to Life: How Genes Drive Development(amzn/b&n/abe/pwll) would have to say.

It wasn’t what I expected at all, but I think readers here will be appreciative: it’s a primer in developmental biology, written for the layperson! Especially given a few of the responses to my last article, where the jargon seems to have lost some people, this is going to be an invaluable resource.

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Generic bumps and recycled genetic cascades

How do you make a limb? Vertebrate limbs are classic models in organogenesis, and we know a fair bit about the molecular events involved. Limbs are induced at particular boundaries of axial Hox gene expression, and the first recognizable sign of their formation is the appearance of a thickened epithelial bump, the apical ectodermal ridge (AER). The AER is a signaling center that produces, in particular, a set of growth factors such as Fgf4 and Fgf8 that trigger the growth of the underlying tissue, causing the growing limb to protrude. In addition, there’s another signaling center that forms on the posterior side of the growing limb, and which secretes Sonic Hedgehog and defines the polarity of the limb—this center is called the Zone of Polarizing Activity, or ZPA. The activity of these two centers together define two axes of the limb, the proximo-distal and the anterior-posterior. There are other genes involved, of course—this is no simple process—but that’s a very short overview of what’s involved in the early stages of making arms and legs.

Now, gentlemen, examine your torso below the neck. You can probably count five protuberances emerging from it; my description above accounts for four of them. What about that fifth one? (Not to leave the ladies out, of course—you’ve also got the same fifth bump, it’s just not quite as obvious, and it’s usually much more tidily tucked away.)

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Diploblasts and triploblasts

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Carl Zimmer wrote on evolution in jellyfish, with the fascinating conclusion that they bear greater molecular complexity than was previously thought. He cited a recent challenging review by Seipel and Schmid that discusses the evolution of triploblasty in the metazoa—it made me rethink some of my assumptions about germ layer phylogeny, anyway, so I thought I’d try to summarize it here. The story is clear, but I realized as I started to put it together that jeez, but we developmental biologists use a lot of jargon. If this is going to make any sense to anyone else, I’m going to have to step way back and explain a collection of concepts that we’ve been using since Lankester in the 19th century.

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The evolution of deuterostome gastrulation

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Do vertebrate embryos exhibit significant variation in their early development? Yes, they do—in particular, the earliest stages show distinct differences that mainly reflect differences in maternal investment and that cause significant distortions of early morphology during gastrulation. However, these earliest patterns represent workarounds, strategies to accommodate one variable (the amount of yolk in the egg), and the animals subsequently reorganize to put tissues into a canonical arrangement. Observations of gene expression during gastrulation are revealing deeper similarities that are common in all deuterostomes—not just vertebrates, but also the invertebrate chordates (tunicates and cephalochordates) and echinoderms.

What does all that mean? If you think of development as a formal dance, the earliest stages are like the prelude; everyone is getting out of their chairs around the ballroom, looking for partners and working their way towards the floor. The dispositions of the dancers are variable and somewhat chaotic, and vary from dance to dance. Once they get to their positions, however, we’re finding that not only is there a general similarity in their arrangements, but they’re all dancing to the very same tune. In this case, one of the repeated motifs in that tune is a gene, Nodal, which is active in gastrulation and shows a similar pattern in animal after animal.

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Scientists…in disagreement!

Yesterday, I reposted an article on homology within the neck and shoulder, which describes an interesting technique of using patterns of gene expression to identify homologous cellular pools; the idea is that we can discern homology more clearly by looking more closely at the molecular mechanisms, rather than focusing on final morphology and tissue derivation. Trust me, if you don’t want to read it all—it’s cool stuff, and one of the interesting points they make is that they’ve traced the fate of a particular bone not found in us mammals, but common in our pre-synapsid ancestors, the cleithrum. They argue from a common cellular origin that this bone has been reshaped into a ridge on our shoulder blade, the scapular spine.

As many readers might know, though, the word “homology,” especially when coupled with a novel technique for its determination, is always good for an argument. This one is no exception.

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Development, medicine, and evolution of the neck and shoulder

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Neck anatomy has long terrified me. Way back when I was a grad student, my lab studied the organization and development of the hindbrain, which was relatively tidy and segmental; my research was studying the organization and development of the spinal cord, which was also tidy and segmental. The cervical region, though, was complicated territory. It’s a kind of transitional zone between two simple patterns, and all kinds of elaborate nuclei and new cell types and structural organizations flowered there. I drew a line at the fifth spinal segment and said I’m not even going to look further anteriorly…good thing, too, or I’d probably still be trying to finish my degree.

Fortunately, Matsuoka et al. were braver than I was and they have applied some new molecular techniques to sort out some of the details of how the neck and shoulder are assembled. This is a developmental study of how the muscles and bones of the shoulder girdle and neck are derived, and what they’ve identified is 1) a fairly simple rule for part of the organization, 2) an explanation for some human pathologies, and 3) some interesting observations about evolution. It is very cool to find a paper that ties together molecular genetics, development, paleontology, and medicine together so inseparably.

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Bicoid evolution

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I’ve written about this fascinating Drosophila gene, bicoid, several times before. It’s a maternal effect gene, a gene that is produced by the mother and packaged into her eggs to drive important early events in development, in this case, establishing polarity, or which end of the egg is anterior (bicoid specifies which end of the egg will form the fly’s head). Bicoid is also a transcription factor, or gene that regulates the activity of other genes. We also see evidence that it is a relatively new gene, one that is taking over a morphogenetic function that may have been carried out by several other more primitive genes in the ancestral insect.

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Bicoid, nanos, and bricolage

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Intelligent Design creationists are extremely fond of diagrams like those on the left. Textbook illustrators like them because they simplify and make the general organization of the components clear—reducing proteins to smooth ovoids removes distractions from the main points—but creationists like them for the wrong reasons. “Look at that—it’s engineered! It’s as if God uses a CAD program to design complex biological systems!” They like the implication that everything is done with laser-guided precision, and most importantly, that every piece was designed with intent, to fill a specific role in an apparatus that looks like it came out of a high-tech machine shop at a Boeing aerospace lab.

This is, of course, misleading. Real organelles in biology don’t look glossy and slick and mechanical; they look, well, organic, with fuzziness and variability and, most importantly, mistakes and slop. What these biological machines look like is not the precisely engineered output of a modern machine shop, but like bricolage. Bricolage is a term François Jacob used to contrast real biology with the false impression of nature as an engineer. It’s an art term, referring to constructions made with whatever is at hand, a pastiche of whatever is just good enough or close enough to the desired result to make do. It covers everything from the sculptures of Alexander Calder to those ticky-tacky souvenirs made from odd bits of driftwood and shells glued together that you can find at seashore gift shops.

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Zygotic genes

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Last week, I wrote a bit about maternal genes, specifically bicoid, and described how this gene was expressed in a gradient in the egg. Bicoid is both a transcription factor and a morphogen. The gene product regulates the activity of other genes, controlling their pattern of expression in the embryo. Today I thought I’d get more specific about the downstream targets of bicoid, the gap genes.

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