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7.3: Lateral Inhibition in Nervous System Patterning

  • Page ID
    14887
  • Not all cells in a nervous system can be neurons. In fact, in our own central nervous systems about half to 3/4 of the cells are glial cells3. In Drosophila, neural progenitor cells (neuroblasts) are only a portion of all the neurectoderm cells. These neuroblasts express proneural bHLH transcription factors including Achaete-Scute complex genes. The Achaete-Scute complex (Ac-Sc) is a cluster of 4 bHLH genes whose protein products form homo- and hetero-dimers to regulate the transcription of neuronal genes. Cells expressing Ac-Sc delaminate from the neurectoderm sheet and eventually give rise to neurons4. Before I summarize Turing pattern-like mechanism for neuroblast specification, I first want to mention that Drosophila neuroblast formation differs in one very important way from a traditional Turing pattern - each neuroblast arises in isolation from other neuroblasts. This patterning is not over an entire tissue but instead is super local, occurring only over a 6-7 cell cluster with only a single cell becoming a neuron (Figure 5)5.

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    Figure 5: Notch/Delta signaling in proneural clusters in Drosophila. In one cell, Delta is activated by Achaete-Scute (AcSc). Delta protein is a ligand for Notch and it activates Notch signaling in cells next to it. In this next-door cell, Notch signaling activates Hairy/Enhancer-of-Split (Hes) expression, which represses AcSc. Without AcSc, Delta is not expressed. In this way, cells next to a Delta expressing cell will not express Delta themselves.

    After proneural cluster specification, random oscillations of Notch signaling pathway components occur until one cell randomly expresses higher levels of Delta, the Notch ligand. This activates Notch signaling in neighboring cells. The activation of the Notch signaling pathway causes the expression of Hes gene Enhancer-of-split, which is a repressor of the AcSc complex. AcSc normally increases the expression of Delta, but in these Notch positive cells where AcSc is off Delta levels begin to go down. In the neighboring Delta positive cell, there is no Notch signaling to turn off AcSc (because of the lack of Delta in all neighboring cells) and Delta levels remain high. In this way, one cell in the proneural cluster is Delta/AcSc positive and the neighboring cells are Notch/Hes positive6 (Figure 3). This system creates one Delta postitive cell in a field via lateral inhibition. In the Turing model, Delta would be the local activator and Notch would be the repressor. Delta activates its own expression by not turning off AcSc and activates Notch in neighboring cells. Unlike the Turing model, Notch and Delta do not need to diffuse for this to work, instead the signal itself is propagated by cell-cell signaling.

    Oscillators and waves - the vertebrate segmentation clock

    Graded morphogens, reaction-diffusion, and lateral inhibition are all ways to generate patterns that are either repeating (like spots and stripes) or polarize a tissue. If you have ever been to the beach or taken a physics course you know that another way to generate a repeating pattern is with an oscillator that outputs a wave function. If you haven't taken physics (or are rusty) the easiest way to think about waves and oscillators is to imagine holding a rope that is tied to a pole. As you move your arm up and down, you act as the oscillator, moving from the high position to the low position. The range of motion of your arm determines the height of the wave. You can make the waves move faster (with higher frequency) by moving your arm more quickly. The speed of the oscillator determines the speed at which the waves move. If your arm moves too slowly, the wave disintegrates quickly and never makes it to the wall.

    Waves and oscillators also occur in biological systems. One of these is the segmentation oscillator in vertebrates. In this case gene expression of Notch pathway genes act as the oscillator. A "clock and wavefront" model has been proposed to describe segmental patterning in vertebrates. Segmentation of the mesoderm surrounding the notochord (the somites) occurs in an anterior to posterior fashion, with somites budding off a posterior zone of unsegmented mesoderm. As new somites bud off, old ones are pushed anteriorly, such that the anteriormost somites bud first. The "segmentation clock" is the oscillator in the pre-somitc mesoderm at the posterior of the animal. A "wave" of hes-class gene expression travels across the presomitic mesoderm (PSM). When it reaches the anterior-most point of the presomitic mesoderm it arrests and the tissue buds off the PSM. The marker telling the tissues when they are far enough anterior are opposing gradients of retinoic acid (RA) in the anterior and FGFs in the posterior. When a wave of hes expression reaches low/moderate levels of each gradient molecule, this signals the tissue to undergo somitogenesis (somite budding)7.

    In the video above, Hes gene expression in the PSM is in blue and in the somites it is red. So the question you might be asking now is "How does Hes act as an oscillator but also travel in a wave?" The wave you are seeing in the video above is a wave of gene expression. The cells themselves move very little. Imagine a stadium full of people doing "the wave." If the wave takes 1 minute to get around the stadium, it can be propogated by a coordinated audience if each person raises their hands for 1 second every minute.

    The people themselves aren't running around the stadium, rather they are "oscillating" between arms up and arms down. Similarly, in the PSM each cell is oscillating between Hes on and Hes off. Just like a stadium wave, cells are testing their local environment to coordinate with nearby cells. When the wave arrives at low levels of FGF and higher levels of RA it stops, just like a wave hitting a wall, and the cells with matching expression patterns bud off the PSM as a somite (Figure 6).

    segmentation.jpg

    Figure 6: Clock and wavefront model. In A, colored blocks indicate gene expression of Notch-pathway effector genes. Cells in the same colored block are coordinated with each other in terms of expression. Each wave across the PSM generates two somites (one on each side). In B, the opposing FGF and RA gradients are indicated by triangles. Orange blocks are somites that have budded off the PSM and blue indicates Notch-pathway effector gene expression. Figure from Carriere and Dale, 20179 published under a CC BY 4.0 license

    How does Hes act as an oscillator and how do cells coordinate with each other? We don't 100% know the answer to this, but there is a lot of evidence that Hes is a cell-intrinsic oscillator and the Notch pathway (controlling Hes expression) helps to coordinate neighboring cells. Hes genes are transcription factors and some Hes genes inhibit their own expression. When protein levels of Hes are high enough, transcription levels go down. These Hes mRNAs and proteins also have a short half life, so when transcription levels go down, they don't stay down for long. As the mRNA and proteins degrade, repression of Hes expression is released and mRNA is made again. Of course, this raises the level of Hes protein, which represses Hes expression. In this way Hes expression acts as an oscillator, as long as it maintains at least a low level of expression and degrades quickly. In mice, degradation of protein occurs within 20 minutes. Stable mutants that last for 30 minutes have dampened oscillatory behavior, just like raising and lowering your arm too slowly when making rope waves7. Oscillation is a intrinsic property of the cells, it can occur in cell culture after serum treatment, but this oscillation is uncoordinated between cells - after a few cycles where all cells show the same periodicity of oscillation, they begin to loose coordination and oscillate on their own wavelength8,9.

    As you can see in the video above, cells in the presomitic mesoderm tend to have the same state of Hes oscillation as their neighbors. This is likely coordinated through the Notch signaling pathway. As we've already seen, the Notch pathway is a juxtacrine signaling pathway with cells next door to each other communicating through cell-membrane receptors. Once activated, Notch undergoes intramembrane cleavage and the cytoplasmic half travels to the nucleus where it releases repression on Su(H) class transcription factors to activate gene expression of effectors like the Hes genes (hairy/enhancer of split genes also called Her genes). By signaling to each other, the PSM cells may exerting positive feedback on their neighbors such that Notch-positive cells induce Notch signaling in next door cells10.