Generating right-left asymmetries

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We're only sorta bilaterally symmetric: superficially, our left and right halves are very similar, but dig down a little deeper, and all kinds of interesting differences appear. Our hearts are larger on the left than the right, our appendix is on the right side, even our brains have significant differences, with the speech centers typically on the left side. That there is asymmetry isn't entirely surprising—if you've got this long coil of guts with a little appendix near one end, it's got to flop to one side or the other—but what has puzzled scientists for a long time is how things so consistently flop over in the same direction in individual after individual. There has to be some deep-seated mechanism that biases developmental events to favor one direction over the other. We know many of the genes involved in asymmetry, but what is the first step that skews development to make consistent asymmetrical choices?

In mammals, we're getting close to the answer. And it looks to be beautifully elegant—it's a simple trick to convert an anterior-posterior difference into a left-right one.

Nonaka et al. have examined the node of the mouse embryo. At the time of gastrulation, the mouse embryo (and the human embryo as well) is essentially a flat, two-layered sheet, with a groove in the middle called the primitive streak, and a dimple at the anterior end called Henson's node. Looking down on the sheet of cells, we'd see something like this:

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This particular diagram is a little cluttered because it's got all those curved arrows all over it; they're there because what's going on at this stage of development is a great deal of cell movement. Cells are moving on the surface layers towards the primitive streak (thick solid lines) and then diving down at the streak into the deeper layers, and migrating from there to various deep places in the embryo (thick dashed lines). This is what gastrulation is about, tucking cells from the surface into a middle layer, creating a three-layered embryo.

This is a cross section through the embryo above, clarifying what's going on. The blue cells are the superficial epiblast (roughly, the ectoderm), yellow is the hypoblast (endoderm), and the cells that have migrated through the streak are colored red, and are going to form mesoderm.

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There's more than just simple movement going on, of course. The cells are also interacting with their neighbors and sending chemical signals back and forth; these inductive signals instruct cells in what tissues they should differentiate into. The node is a particularly important place for these signals, and cells going through there will become axial mesoderm—central structures like the notochord that will define the midline, and also will specify the formation of essential tissues like the nervous system.

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So the node is important as a critical structure for setting up axial structures. It's also important for generating early asymmetries.

To the right is a scanning EM of a mouse node. Don't get too confused; the figure labeled B rotated so left is on top and bottom on the right, but the area we care about has an arrow pointing to it. Zooming in on that area of the node in C, you can see the tops of the epithelial cells looking vaguely like cobblestones, with white strings scattered around. These are ciliated cells, and the strings the whip-like cilia that would be swinging around in a clockwise rotation if the cells were alive. You can watch a QuickTime movie of node cilia to see it in action.

When you watch those cilia spin around, here's the subtle but important thing to look for: their paths don't form perfect circles, which would indicate that they are pointing straight up at you, but are instead deformed to varying degrees, showing that they are tilted at an angle…and they are all tilted in the same direction, towards the posterior end of the embryo.

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Trajectory of Node Cilia Movement (A) Trace of node cilia in enhanced DIC images after background subtraction. Positions of root are indicated in black, and tip in blue, green, and orange. Most cilia have a pattern consistent with the projection of a tilted cone (blue and green, see text) whereas some cilia move in a D-shape (orange). A, P, L, and R refer to anterior, posterior, left, and right sides of the node, respectively. The direction of cilia rotation was clockwise (arrows). (B) Relationship between essentially rotatory movement of cilia and their projected images at various tilt angles.

That tilt is what generates the left-right asymmetry. The tilt isn't asymmetric—all of the cilia are aimed just a little bit posteriorly, rather than straight up—but because the cilia are also rotating in a clockwise direction, it generates unequal lateral forces.

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Flow Generation Mechanism. Circular clockwise motion of a cilium can generate directional leftward flow if its axis is not perpendicular to the cell surface but tilted posteriorly. Due to distance from the cell surface, a cilium in the leftward phase (red arrow) drags surrounding water more efficiently than the rightward phase (blue arrow), resulting in leftward force in total (purple arrow).

Because of that tilt, the left-to-right stroke drags along the surface of the cell, and is less efficient at generating fluid flow. The right-to-left stroke, on the other hand, swings up and away from the cell and into the medium, and effectively pushes fluid to the left. It's a very elegant way to create handedness using an existing anterior-posterior axis to amplify the chirality of the rotating cilia into a directional shift.

The authors cleverly made a mechanical model of cilia with rotating wires in a viscous silicone medium (another QuickTime movie here), with glitter used as a marker that could be seen streaming specifically to one side. That's how this would work in a real animal: start with a symmetrical embryo which is secreting diffusible molecules from a central point like the node, and then the rotation of the cilia sends the bulk of those molecules streaming to just the left side. Those molecules then induce biases in the pattern of differentiation of one side over the other, leading to all our familiar internal asymmetries.

It should also be obvious why a rare genetic disease, Primary Ciliary Diskinesia, which causes defects in ciliary motors that prevent them from rotating, is also associated with a condition called situs inversus (not all cases of situs inversus are caused by PCD, however), in which humans have their internal asymmetries reversed—heart larger on the right, appendix on the left, etc. If the rotors aren't spinning properly, they don't generate the sideways force, so the molecules are randomly spread to both sides…and in those cases it's just luck which determines which way the asymmetries will form.


Nonaka S, Yoshiba S, Watanabe D, Ikeuchi S, Goto T, et al. (2005) De novo formation of left–right asymmetry by posterior tilt of nodal cilia. PLoS Biol 3(8): e268.

More like this

Our hearts are larger on the left than the right

???

et al - it is the left side of the heart that pumps blood to the body (right side pumps blood to the lungs to lose CO2 and gain O2). Getting blood to the body requires more pressure, thus the left side of the heart is larger than the right. See here http://www.wellesley.edu/Biology/Courses/111/ForOval.gif for an amination.

By ctenotrish (not verified) on 30 Aug 2006 #permalink

or an animation, depending on what you call them in your neck of the woods . . .

By ctenotrish (not verified) on 30 Aug 2006 #permalink

Okay, that's pretty neat. Reminds me of the conceptual weirdness that surrounds early-universe symmetry-breaking; indeed, I wonder if a similar mathematical model of "spin against a tilted potential surface" might be responsible for something that nature. However, another symmetry had to break first, so I put the question back to the biological inspiration for my model:

where'd the anterior/posterior symmetry difference come from?

That is very cool! Eons ago when I was studying developmental biology at the U of M--TC, I worked in a lab that was studying heart development in frogs. Years later, I understand this much better--thanks!

And the cause of the unidirectional rotation of the rottors lies in the physical structures of the proteins that drive them.

Because proteins are always asymmetrical molecules, protein-based machinery acts asymmetrically. Any protein-based molecular motor that drives circular motion will necessarily always drive it in the same direction. Whether that motion is clockwise or counterclockwise depends on the evolutionary 'design' of the motor.

So I think this means that the macroscopic asymmetries of our bodies arise directly from the molecular asymmetries of our proteins. Nice.

(Yes, I know that the motor driving the bacterial flagellum occasionally reverses direction briefly. I don't know how this is done, nor whether it's a true reversal of the spin. I'll see what I can find out.)

Me again. I found a review by Howard Berg (Ann. Rev. Biochem vol. 72, pp 19-54) discussing how bacterial flagella rotate. He's THE expert.

Only some flagella can reverse. It's a genuine reversal of the direction the flagellar filament rotates, but it's not a mirror-image reversal of the underlying proteins and processes. When the signal to reverse is sensed, the proteins shift into a different but still very asymmetric conformation in which they generate torque in the opposite direction. This forces the rows of (asymmetric) proteins making up the flagellar filament to twist around each other in a different way, changing the shape of the filament and interfering with normal forward motion.

Very interesting. Thanks for information Rosie!

By Paguroidea (not verified) on 30 Aug 2006 #permalink

Re: the heart asymmetry thing--however, before you're born, it is the right side that has the higher pressure gradient. It's not until you're breathing air and pulmonary resistance decreases that the left side becomes significantly larger than the right. You can see the gradual change by following serial electrocardiograms in infants--they start out with right-axis deviation (implying that the right heart has the greater muscle mass) and then the axis slowly drifts leftward until it reaches what is considered normal. And then if you end up developing lung disease, pulmonary resistance increases, and you can actually end up with a right heart larger than your left. So clearly it's not just genes alone influencing this particular asymmetry.

Amazing stuff! My brother has complete situs inversus but, to the best of our knowledge, does not have primary ciliary diskinesia -- at least, he's never demonstrated the usual symptoms. So I can't help but wonder, when you mention "not all cases of situs inversus are caused by PCD", if any causes other than PCD have been characterized at all.

PZ -- if you ever dare to delve into the deeper layers of asymmetry then your best bet is the book "Doubt and Certainty" by particle physicist Sudarhar (1998).

I won't comment on your recent water debacle being a Jungian archetype of the amplitude-intensity paradox in macro quantum chaos.

Also please read "Quantum Evolution" by professor McFadden.