Transcription factors and morphogens

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In my previous comments about maternal effect genes, I was talking specifically about one Drosophila gene, bicoid, which we happen to understand fairly well. We know its sequence, we know how it is controlled, and we know what it does; we know where it falls in the upstream and downstream flow of developmental information in the cell. So today I'm going to babble a bit more about what bicoid is and does, and how it works.

Bicoid is a transcription factor.

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The diagram above illustrates what a transcription factor (in this case, called "gene X") is. Gene X is transcribed to form a strand of messenger RNA, that is then translated by the cellular machinery into a protein, the red ball in the cartoon, transcription factor X. So far, this is just the central dogma, and is pretty much the same routine executed for all genes. The function of a transcription factor, though, is to migrate back into the nucleus, and bind to specific regions of DNA. When the transcription factor binds to one of these regions, it affects the transcription of other genes; in this example, transcription factor X turns on genes A, B, C, and E, and turns off gene D. There are many transcription factors active at any one time in a cell, that may also bind to the same target genes, and may have conflicting or competing effects on gene activity.

It gets more complicated. Genes A, B, C, D, and E could also be transcription factors, that may feed back on each other (gene B could, for instance, also turn on gene C) and on other transcription factors not directly regulated by gene X (genes F, G, and H, perhaps). Gene X is also regulated by transcription factors—and some of the genes it controls could feedback and regulate gene X itself! These different interconnections between the many regulatory genes, if diagrammed fully, would form an intricate webwork, much more complex that the few arrows in this cartoon.

Bicoid is also a morphogen.

A morphogen is a diffusible substance that specifies the fate and activity of developing cells by its concentration. Bicoid exists in normal embryos in a steep concentration gradient, from high levels at the anterior end to very low levels at the posterior end. Cells along the length of the embryo can 'read' the concentration of bicoid and use that to determine what they should do—if bicoid is high in its local environment, the cell 'knows' that it should make a head, and if the level is low, it 'knows' it should make a tail.

How does a cell 'read' or 'know'? Another complication not shown in the cartoon of transcription factors above is that each gene has multiple regulatory sites that can bind multiple transcription factors, and that binding of the transcription factor isn't exactly as simple as a binary on/off switch. The cell may need a certain number of transcription factor X molecules to be present in order to turn on gene B. There may also be competition with other factors, transcript factor Y, for instance, that are trying to turn gene B off.

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The concentration of bicoid is what determines the role cells will play in development. This diagram illustrates what happens if the concentration of bicoid is changed in the embryo by giving the mother more and more copies of the bicoid gene; at the top, the mother has only one functioning bicoid+ gene, in the second picture, she has two, in the third, four, and in the fourth, 6 copies. The red line in the picture marks the position of a structure called the head fold—everything to the left of the line will make the fly's head, and everything to the right will make its thorax and abdomen. As you can see, the more bicoid you put into the embryo, the steeper its gradient of concentration, and the bigger the fly's head will be.

Something that is very important to keep in mind is that genes like bicoid are definitely genetic components that contribute directly and demonstrably to the development of form. We do not hesitate to say that this gene, and others, are essential determinants of morphology; modify the gene, or modify the regulatory control of this gene, and you can get drastic changes in the shape of the fly. However, the genes alone are not enough. What confers specific functional properties on the expression of the gene is also its initial distribution—what is essential to form a healthy fly is 1) the bicoid gene product 2) distributed in a concentration gradient. That gradient is an important piece of information. The gradient isn't really explicitly described anywhere in the genome, either—it's an example of an emergent property, something that arises from complex interactions between the genome, between cells, and with the environment.

Another way to think of it is that if we wanted to make a fly completely from scratch, synthesizing all the components of the egg from chemicals, having the sequence information of the genome is not enough. In addition to making the strands of DNA and surrounding it with membranes and packing the cell with water, salts, and various proteins, we'd have to make sure this one factor, bicoid, was present in a particular pattern. And bicoid is only one of many transcription factors that are present in precisely ordered distributions in the egg.

This has been a very general description of what transcription factors are. In the next day or two, I'll try to describe more specifically exactly what genes are downstream of bicoid, and how more details of fly morphology are regulated.

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Very interesting. As a complete non-scientist (I dropped the subject at 14 but now wish I hadn't)I appreciate these lucid explanations in bite-sized chunks.

I read science books from the library, but a whole book at this level of detail is too intimidating, often assuming knowledge I don't have, and, in my experience, almost never as clearly explained as this post

By Kiwi Dave (not verified) on 09 Jul 2006 #permalink

You state:

How does a cell 'read' or 'know'? Another complication not shown in the cartoon of transcription factors above is that each gene has multiple regulatory sites that can bind multiple transcription factors, and that binding of the transcription factor isn't exactly as simple as a binary on/off switch. The cell may need a certain number of transcription factor X molecules to be present in order to turn on gene B. There may also be competition with other factors, transcript factor Y, for instance, that are trying to turn gene B off.

Essentially, what you are describing here is the upstream promoter region. This is what Sean Carroll has refered to in popular literature as a "combinatorial switch," and what may be thought of as a function which takes several input to determine its output, namely, the expression of the protein which it is a promoter for. In earlier literature, this had been analyzed largely in terms of boolean operations, but it is becoming obvious that expression isn't a matter of simply being on or off, but a matter of degree.

Interestingly, we have been discovering that the same gene may have more than one promoter (a second, "alternate" promoter), and to add to the complexity, there may be promoter chains.

On a somewhat related note, there has been a development in terms of bat wing evolution. If you will remember, the lengthening of the digits by a factor of 6 to 8 and of the "forearm" by a factor of two had been traced back to the increased expression of Bone Morphogenic Protein 2. The same set of researchers have now traced this back to a shift in Hoxd13 expression towards the posterior, which leads to increased expression of Hoxd10-11. This shift would appear to be the result of the upstream regulation regulation of Hoxd13, possibly in terms of Gli3.

For more on this, please see:

Hoxd13 expression in the developing limbs of the short-tailed fruit bat, Carollia perspicillata
Chih-Hsin Chen, Chris J. Cretekos, John J. Rasweiler IV, and Richard R. Behringer
Evolution & Development 7:2, 130-141 (2005)

Woohoo! Emergent properties! I can't believe after all this time that many philosophers find them contentious, since even elementary chemistry (think molecular shape) illustrates the notion. Biology illustrates them in spades, and here's another example.