Hedgehog signaling pathway

Definitions & Key takeaways

The Hedgehog signaling pathway is a critical regulator of embryonic development. It controls the growth and patterning of tissues and organs during development. The pathway is activated when hedgehog proteins bind to a receptor on the cell surface, triggering the activation of genes involved in growth and patterning.

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The hedgehog signalling pathway is a pathway based on three specific proteins called the hedgehog proteins. The most well studied of these proteins is the Sonic hedgehog protein which plays a key role in structuring the general shape of the body, called patterning.
During the third week of development, a solid rod of mesoderm called the notochord forms at the midline of the embryo. The notochord is extremely important during early development because it helps influence how the embryo folds.
It also guides how the various tissues differentiate and develop so that the embryo ends up with two arms, two legs, and one head, instead of some other combination.
The way that works is that groups of cells within the notochord secrete a few proteins - Desert hedgehog protein, Indian hedgehog protein, and Sonic Hedgehog protein called Shh for short.
Desert and Indian hedgehog protein were named first, and Sonic was named a bit later - it was named after the cute, fast-moving video game character - Sonic the Hedgehog.
The hedgehog proteins are ligands, meaning they’re molecules that move from one cell over to another and facilitate communication - like letters that a cell might send to another cell around the corner.
Early in development, the notochord sends all three hedgehog proteins out to undifferentiated cells throughout the entire embryo.
When the Sonic hedgehog protein gets released it slowly diffuses through the interstitial liquid and binds to a receptor called Patched which can be found on the cell membranes of embryonic cells.
The Patched receptor inhibits the embryonic cell from differentiating, but Sonic hedgehog protein inhibits patched, meaning it inhibits the inhibitor!
Without the inhibition of Patched, the embryonic cell starts to activate specific genes that allow it to differentiate. But every embryonic cell doesn’t differentiate in the same way - some might activate genes that allow them to be part of a leg, whereas others might activate genes that allow them to be part of an ear.
The precise set of genes that get expressed in one cell versus another cell depend on how much Sonic hedgehog protein reaches the embryonic cell, and how long the embryonic cell is exposed to Sonic hedgehog protein.
One way to think about this is that it’s the cumulative dose of Sonic hedgehog protein that determines which genes get expressed and ultimately what each embryonic cell turns into.
When Sonic hedgehog protein is released by the notochord, it diffuses throughout the embryo, forming a concentration gradient.
To better visualize this, let’s say each one of these squares in the grid is an embryonic cell. The embryonic cells nearest to the notochord get exposed to a high dose of Sonic hedgehog protein and embryonic cells further away are exposed to a lower dose of Sonic hedgehog protein.
In other words, there’s a concentration gradient. It’s similar to what happens when a drop of red dye falls in a bucket of water, the areas closest to where the dye is dropped will be red, and the red color fades the further you move away.
So the amount of hedgehog protein that binds to an embryonic cell tells that cell where it is in three dimensional space relative to the notochord, which is the source of the hedgehog protein.
So for example this cell, since it has 2, might know to differentiate into brain tissue, whereas this one, since it has 3, would differentiate into an arm.
Now if the notochord cells keeps making Sonic hedgehog protein, it might seem like over time the entire chessboard would be filled with the protein, but that doesn’t happen because over time the proteins naturally degrade.
Ok so now cells can identify where they are in relation to the notochord, but a cell over here would still have no way of distinguishing itself from a cell over here, since they both got the same amount of sonic hedgehog protein.
And many of the cells that are really far away might not get any proteins at all. That’s why it’s helpful that the notochord secretes a lot of these different Hedgehog proteins.
Let’s draw in Desert hedgehog, represented as a green dye, which creates a gradient coming from the bottom of the notochord.
Then let’s draw in Indian hedgehog, represented as a red dye, that creates a gradient coming from the middle of the notochord.
Now each square of the board have been exposed to varying levels of the three different proteins, with each square getting a relatively unique combination.
In fact, if I told you that a cell with two blue and two red proteins and and no other proteins will give rise to the arm, then you can see which ones those would be - this one on the left, and this one on the right.
In fact, that’s why the two sides of our bodies are largely symmetric. All right, as a quick recap, the notochord makes various proteins, including Sonic hedgehog protein which binds to the Patched receptor on embryonic cells.
Sonic hedgehog protein diffuses through the embryo creating a concentration gradient. This, along with other proteins released by the notochord, help each embryonic cell identifies exactly where it is in three-dimensional space.