How Flies Control Eyes Size

Getting left-right symmetry doesn’t just happen.
It is regulated by specialized machines.

 

A tiny fruit fly, just a few millimeters in length, has a problem. Its eyes have to match. It couldn’t fly straight if one eye were bigger than the other. The problem grows in complexity when one realizes that its eyes are compound eyes, made up of 800 separate light-sensing units, called ommatidia. For such a tiny organ on a tiny fly—unless a mutation disturbed the developmental process—the precision of the completed eye is phenomenal. In 2011, Justin Kumar wrote in Developmental Dynamics,

The Drosophila melanogaster compound eye is a simple nervous system consisting of approximately 800 unit eyes or ommatidia that are assembled into a hexagonal array of striking precision … A typical eye will contain roughly 32–34 interlocking vertical columns of unit eyes. The number of ommatidia per column is graded across the eye and this gives the eye an overall oval or egg shape. The compound eye also contains a set of mechano-sensory bristles, which are located at the anterior vertex of each ommatidium.

All this sophisticated precision, remember, grows from a single cell, the zygote. Thousands of cell divisions later, after pupation, an adult fruit fly emerges with a pair of eyes that are mirror images of each other, each with 800 ommatidia. How does that happen?

Building 3-D Symmetry

We tend to take for granted the symmetry of left and right sides of an organism. Our own eyes, hands and feet are mirror images of each other, but are essentially identical, working together. But we must not take the symmetry for granted. It doesn’t just happen. If genetic programs did not work, there would be trouble: misshaped eyes, mismatched eyes, or blindness. These genetic programs, moreover, must work in the same way on each side simultaneously, even though separated by a distance. How does the fruit fly’s left eye know what the right eye is doing?

A recent paper gives a glimpse in how the required precision is achieved as the compound eye grows on the heads of these tiny flying machines.

Size precision in insect eyes (PLoS Biology, 31 Jan 2024). In this Primer, Marco Milán from the Barcelona Institute of Science and Technology discusses a paper by Casares et al. in the same journal (see below) that explains how the eyes of a fruit fly attain “size precision” as they grow by a controlled process that reduces “fluctuating asymmetry” (FA), or a wobbly mismatch of size and shape. In effect, the growing cells of the eye do The Wave:

A new study unravels an organ-intrinsic mechanism of growth control in the developing fly eye that confers size precision through feedback interactions between proliferating and differentiating cells. This mechanism reduces eye size variability between and within animals, thus contributing to the symmetry between contralateral eyes and having a clear potential impact on eye functionality. In the growing eye primordium, a wave of differentiation moves anteriorly, whereby proliferative progenitors located anterior to the wave are recruited as differentiating retinal cells that exit the cell cycle (Fig 1). When the wave reaches the anterior-most region of the primordium, no remaining progenitors remain in the tissue, and the final eye size is attained. The movement of the differentiation wave relies on the activity of 2 morphogens [shape generators], the BMP homolog Dpp and Hedgehog (Hh), which are produced by differentiating retinal cells that signal anteriorly to nearby proliferating cells to recruit them as new differentiating retinal cells. In this regard, Casares, Ares, and colleagues reveal the role of Dpp in regulating eye size by blocking the apoptosis of progenitor cells and present evidence that this mechanism plays a key role in reducing eye size variability and FA.

A simplified diagram of the process is shown in the open-access paper. The developmental program, in short, uses two morphogen proteins (Dpp and Hh) in a signaling wave across the progenitor cells in the developing eye. These morphogens tell the next cells in line to either differentiate into retinas or die by apoptosis (programmed cell death)*. When no more progenitor cells are left, the eye is complete and differentiation ceases.

*Apoptosis is a common method in embryology to help shape organs. It is used in a human embryo’s growing hands, for instance, to reduce the webbing between fingers. The process of apoptosis is programmed and responds to a signal cascade, releasing proteins that act like cutting tools to dismember the cell. All the parts are recycled.

Only a Glimpse

But surely this all represents only a fraction of what occurs. The eye is a 3-dimensional structure, with multiple rows growing simultaneously across a curved space. Each ommatidium, furthermore, is a tall structure that must grow orthogonal to the direction of the developmental wave. The ommatidia in each row cannot be the same size, because they need to fit with other rows on a curved surface.

Not only that, each unit eye or ommatidium has to grow a lens, a retina with light-sensitive proteins, and neurons connecting to the brain. And between the ommatidia, touch-sensitive bristles must grow, not getting in the way of the eyes, but protecting them from dust and informing the fly about any objects the bristles encounter.

In the finished eye, the ommatidia and bristles fit against one another tightly. Each one is wired to the brain to produce a composite image with near 360° coverage. Most of the time, for billions of fruit flies, this process works perfectly.

Look again at the photo of the fruit fly’s eyes, and wonder. How could such a marvel grow from a single egg cell?

Dr Milán tells how the new study builds on previous work about how the fruit fly’s wings grow:

In developing multicellular organisms, the final size of each organ is tightly regulated by chemical and mechanical cues. Drosophila provides an excellent system in which to genetically identify and molecularly dissect those cues. The exquisite regulation of organ size in this animal is exemplified by the reduced variability observed between the left and right wings of the same insect….

He cannot help but wax poetic about these humble flies, and how they are sculpted by morphogens and apoptosis to create kinetic art worthy of royalty:

Apoptosis has previously been shown to contribute to reducing size variability and FA in adult wings. Thus, apoptosis appears to impact the ability of flies to be the queens of the air through precise regulation of the size of their left and right eyes and wings.

… and legs, and antennae, and all the other parts. “Queens of the air”: a label most of us would never use to describe pests we shoo away. Like Michael Dickinson wrote years ago, think before you swat!

Where Are You, Darwin?

Feedback control of organ size precision is mediated by BMP2-regulated apoptosis in the Drosophila eye (Navarro, Cesares et al., PLoS Biology, 31 Jan 2024). This is the open-access paper with the details of fruit fly eye development. Let’s investigate whether they had any use for Darwin’s Stuff Happens Law to explain all the complexity they describe:

In Drosophila, the end point of eye development is reached when all retinal progenitor cells differentiate, as differentiation is accompanied by the exit of the cell cycle. Three features should have resulted in a strong evolutionary pressure to maximize the precision in eye size: First, size impacts vision directly, as image resolution and contrast sensitivity is proportional to the number of light sensing units in the eye; second, making and maintaining the eyes is energetically very expensive, so there is a pressure to match eye size to vision needs; and third, left and right eyes must survey a symmetrical part of the space, so eye asymmetry, which could be driven by developmental noise, should be minimized. In this paper, we investigate the mechanism by which the Drosophila eye ensures its size precision as an example of organ size control.

That’s it. That’s their only reference to evolution. Flies needed precisely-sized eyes, so the Blind Tinkerer, out of mercy, gave it to them. Flies needed to see, so evolution gave them eyes. Flies needed eyes their eyes to be clear, so evolution minimized developmental noise.

How, you ask, did Evolution do this? She put pressure on their eyeless, wingless ancestors, telling them, ‘Get matching eyes and wings, or else! What do you want, to live blind on the ground all the time?’ Waving her magic wand, Evolution called on Popeye to punch their lights on.

Isn’t evolution wonderful? Isn’t Charley’s theory marvelously helpful in explaining things? Doesn’t it give you understanding, insight and wisdom? How would science ever manage without the Stuff Happens Law? But if you whisper, Intelligent Design, King Charley will say, “Off with your head!”

But enough about the corruption in King Charley’s castle. We hope this new research increases your awe about the extent of engineering prowess exhibited in living creatures. We hope it prompts you to give honor where honor is due: to our omniscient, all-powerful Creator.

Yesterday we looked at large-scale creations: the magnificent spiral galaxies. Today it was about humble fruit flies, darting about so small they can hardly be seen. From tiny to mighty, all creatures of our God and King should prompt us to lift up our voice and with us sing ‘O praise Him! Alleluia!’