BIOL 104 Lecture Notes - Lecture 8: Apical Ectodermal Ridge, Fibroblast Growth Factor, Limb Bud
Limb Development The development of a complex structure like the human arm is an excellent model
for understanding how spatial-specific gene expression can control organized growth and patterning.
Ultimately, genes lead to cell-cell signaling. When two cells want to communicate, one cell releases a
signaling factor (often a protein) that binds to a receptor on the surface of the other cell. Activation of
the receptor at the cell membrane activates a cascade of events in the cytoplasm that amplifies the
signal (think of a game of telephone where one person tells two and those two people tell two
people….). Fiall, the sigal eters the ucleus where gees are tured o/off.
This is how cells in the embryo know what to do. We discussed two signals in the developing limb.
#1 - FGF from the AER The limb bud extends from the sides of the embryo and the outer rim of tissue is
called the Apical Ectodermal Ridge (AER). Removal of the AER causes the limb bud to stop growing.
Furthermore, addition of a second AER to another limb causes extra growth of the limb. This indicated
that the AER secretes molecules that promote the outgrowth of the limb.
We know that Fibroblast Growth Factor (FGF) is specifically expressed in the AER. Evidence that FGF is
the mystery growth promoting protein comes from the following experiment. -removal of the AER = no
growth -removal of the AER + FGF = growth We can also take FGF away to determine whether FGF is
required for normal limb growth.
The mesenchyme proliferates in response to the FGF signals coming from the AER. The underlying
mesenchyme (loose tissue) tells the limb to become leg or arm. If you switch the arm mesenchyme with
leg mesenchyme a leg will grow instead of arms.
#2 - Sonic Hedgehog from the ZPA The limb not only has to grow out from the side of the embryo, it has
to be patterned across several axes. The anterior (head)-posterior (tail) axis is highlighted by the fact
that your thumb is only on one side of your hand. Your fifth finger is on the other side. This is
determined by the Zone of Polarizing Activity (ZPA).
The ZPA was discovered by accident. John Saunders transplanted the ZPA, a small region in the
posterior limb bud to the anterior region. This resulted in a mirror-image duplication of the limb.
Instead of a 2-3-4 finger order, he saw a 4-3-2—2-3-4 finger order.
In the early 90s it was shown that the Sonic Hedgehog gene is specifically on in the ZPA region. Evidence
to show that Soic is the ZPA protei iicked Sauders’ eperiets. Although Soic is orall
expressed only in posterior cells, they induced Sonic expression in anterior cells also. The result was a
mirror-image duplication of the limb (the same as the ZPA transplant studies).
FGF expression in the AER and Sonic expression in the ZPA is driven by the collection of transcription
factors binding to the promoter, silencers, and enhancers. In the case of Sonic, there is a specific
mutation in one enhancer that has been shown to induce polydactyly in a wide variety of animals,
including humans.
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Document Summary
Limb development the development of a complex structure like the human arm is an excellent model for understanding how spatial-specific gene expression can control organized growth and patterning. When two cells want to communicate, one cell releases a signaling factor (often a protein) that binds to a receptor on the surface of the other cell. Activation of the receptor at the cell membrane activates a cascade of events in the cytoplasm that amplifies the signal (think of a game of telephone where one person tells two and those two people tell two people . ). Fi(cid:374)all(cid:455), the sig(cid:374)al e(cid:374)ters the (cid:374)ucleus where ge(cid:374)es are tur(cid:374)ed o(cid:374)/off. This is how cells in the embryo know what to do. We discussed two signals in the developing limb. #1 - fgf from the aer the limb bud extends from the sides of the embryo and the outer rim of tissue is called the apical ectodermal ridge (aer).
