One of my favorite signal transduction pathways (what? You didn’t know that true nerds had favorite molecular pathways?) is the one mediated by the receptor Notch. Notch is one of those genes in the metazoan toolkit that keeps popping up in all kinds of different contexts—it’s the adjustable wrench of the toolbox, something that handles a general problem very well and therefore gets reused over and over again, and the list of places where it is expressed in Drosophila is impressive.
The general problem that Notch solves is the resolution of a binary decision in cell fate, one where a few dispersed cells in a field of otherwise undifferentiated cells (called an equivalence group) must acquire a new fate, and further, must communicate to neighboring cells that they should follow a different fate. It’s like the problem of selecting a team captain in sports: there might be different strategies for picking such an individual, but one thing that must be done is to inform everyone on the team when the choice has been made, and suppress competing captains from emerging. Notch does that job of spreading the news.
The diagram below illustrates the process. In an equivalence group of cells (all yellow), one cell acquires a unique fate (red), and subsequently enforces the general fate on all of its neighbors by a process called lateral inhibition. Notch is the receptor molecule at the heart of that lateral inhibition. It does its job by interacting with ligands, such as Delta, Serrate or Lag2 (DSL for short).
How does Notch do this? Remember, initially all of the cells in this tissue are an equivalence group—they’re all expressing the same genes, including Notch and, for instance, Delta. All of the cells are signaling to each other with Notch and Delta.
There is a kind of tension here, though, a dynamic instability. When Notch is activated by binding Delta, what it does is stimulate a pathway (Suppressor-of-hairless (Su(H))→Enhancer-of-split (E(Spl))) that turns off the Achaete-Scute gene complex (AS-C)—by the way, another reason I like this pathway so much is the baroque names of the elements) which regulates the expression of Delta. In a field of perfect, uniform, determinate cells, what ought to happen then is this: all the cells would interact with each other with Notch and Delta, Notch would turn off Delta production in all of the cells, all of the Notch receptors would then be unbound, releasing the cells from inhibition, Delta would be produced, all of the cells would interact with each other with Notch and Delta, and the cycle would continue. Boring!
Of course, cells are not perfect, uniform, and determinate. In real life, something like the situation diagramed below arises.
The first panel is the situation in the equivalence group: all of the cells are expressing both Notch and Delta.
The second panel is where things get interesting. The cell on the top has acquired a slight edge, and is expressing its Achaete-Scute complex more strongly than the cell on the bottom. This could be a result of some entirely random phenomenon—the cell started expressing those genes a little earlier, a few extra molecules made it through processing, by chance its Notch receptors were bound to slightly fewer ligands from its neighbors—or perhaps some other more deterministic process upregulated Delta in this particular cell. Whatever the difference, the cell on top is signaling via Delta more strongly than its neighbors, which means the neighbors activate the Su(H)→E(Spl) pathway more strongly, and therefore produce less Delta ligand. This produces a runaway loop, so that cells that initially had a slight edge in Delta signaling produce a stronger and stronger signal, and all the cells that were initially at a slight disadvantage are more and more suppressed.
The end result is in panel 3. All of the cells are producing Notch receptor, but only one is now producing the Delta ligand, and that ligand keeps all the neighbors in a Delta-free state. This is the outcome of lateral inhibition—in this case, a field of cells with a scattered subset of non-adjacent cells with a different pattern of gene expression.
One specific example where this takes place is in the insect neurectoderm, illustrated below, where Notch is essential in mediating the early fate decision in whether a cell will become a neuroblast, the progenitor to the neural elements of the central nervous system, or an epidermoblast, which will make the structural and supporting cells of the tissue. This is a situation where the desired end result is scattered neuroblasts surrounded by supporting cells, and is the classic place for Notch to play a role.
A recent short review on Science gives a summary of the details of the signal transduction pathway for Notch. It’s delightfully elaborate, and has a nice diagram I’ll be using in my class today…and now you know why I’m suddenly babbling about this particular receptor.
In order to do its job, Notch is being constantly churned over in the membrane. The response to binding the Delta/Serrate/Lag-2 ligand is to be cleaved by an extracellular enzyme, releasing a fragment, the Notch intracellular domain (NICD), which is then further processed by presenilin, ubiquitinated, and transported into the nucleus, where it cooperates with a family of transcription factors (CBF1, Su(H), and Lag1, or CSL) to regulate gene activity. As you can see in the diagram, there’s also continuous recycling and degradation of all of these proteins—cells are not static!
Despite the complexity of this pathway, though, this is not at all unusual, and isn’t even the most elaborate pathway I’ve seen—this is typical. And before anyone rushes to argue that this kind of complexity is an obstacle to evolution, I’ll mention that signal transduction elements that modify patterns of gene expression are not unique to animals, and that this general kind of activity is common in the bacterial world, too. The toolkit our cells use evolved first in single-celled organisms, and these are universal solutions to the problem of modifying gene activity in response to conditions in the environment.
In addition, welcome to the strange world of the cell, which IDists to the contrary, is not a world full of analogs to the machines of human culture. Look at the constant breakdown and turnover and synthesis of this signal. Michael Behe likes to compare this sort of thing to traffic lights, but in our macro world, traffic lights don’t work by constantly glowing red, being smashed to signal ‘go’, and stopping traffic again by getting re-manufactured and hung back out in the intersection. That is a standard way of managing signaling in a cell, however.
Ehebauer M, Hayward P, Arias AM (2006) Notch, a universal arbiter of cell fate decisions. Science 314(5804):1414-1415.