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Lecture 36

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Biology (Sci)
BIOL 300
Siegfried Hekimi

rd BIOL 300 December 3 2012 Lecture 36 Dr. Shock We can divide paracrine signaling into two type: • Binary (e.g. EGF signaling), where the pathways is simply on or off • Gradient (e.g. DPP, TGF-bet), meaning you can have different responses depending on ligand concentrations Gradient signaling involves creation of different responses in different cell types, depending on the concentration of ligand they are exposed to • This method of signaling is economical (the same ligand can be used for many different cells) The theory of gradient signaling was proposed in 1952, called the French Flag signaling because the genes resulted in production of red, white and blue • Each cell in the row would have the potential to turn into either red, white or blue cells • Because of the gradient of ligand depending on where it was released, some cells having higher ligand concentrations would turn blue, medium would be white, and low levels would be red • Each cell has a threshold concentration which would cause development into a certain color How could a TF like SMAD (in the TGF-beta pathway) be able to go through a pathway like this on a molecular level? • The blue gene could have very little binding sites for phosphorylated SMAD, with non-perfect consensus, meaning you would need more active SMAD (i.e. more ligand) in order to be activated • Similarly, the red gene would have more consensus sites, with better consensus to the phosphorylated SMAD, to allow it to work at much lower concentrations of ligand • The white gene would be somewhere between these two extremes Factors needed for gradient signaling: • Competence, i.e. all the cells are ale to respond to a gradient of the ligand • This means that all cells would have to express the receptor for the ligand • Need a localized source of the ligand • A ligand can be continuously removed (either through bulk membrane flow endcoytosis or other mechanisms like cleavage or degradation) • You do not want to have activity-mediated receptor endocytosis; this would cause the response not to last long 1 rd BIOL 300 December 3 2012 Lecture 36 Dr. Shock It is believed that all the conditions above hold true for the Dpp (TGF-beta) pathway To establish gradient signaling, we have to find a pathway: • That regulates two or more target genes • The ligand regulates these genes in a concentration dependant manner • Can be differentiated from relay signaling • Relay signaling involves a signal that begins at one cell, activating gene A, which will cause release of a ligand (e.g. EGF) which will activate gene B in the cell adjacent to it, which will trigger a domino effect causing activation of multiple different genes in the adjacent cell • It can be deceiving because the final product looks a lot like gradient signaling; it’s difficult to differentiate between the two experimentally • Relay signalling involves 2 or more pathways, while gradient signaling involves only one pathway an one releasing cell (or a group) This was first solved in 1996 in Drosophila in development of adult organs In the larvae, you have tissues, or epithelial sheets, known as imaginal discs, which will later form the adult organs • This is a nice system because each organ is organized into a single layer, and not complicated 3D networks seen in many mammals, making it easier to study • This imaginal disc will be patterned in such a way that the fly will eventually know which parts of the disc form which parts of the organ The Dpp/TGF-beta patway supposedly mediates gradient signalling in the wing disc • In order for this to be true, there would need to be a localized signal of Dpp, which indeed there is; a single layer or 2 rd BIOL 300 December 3 2012 Lecture 36 Dr. Shock group of cells on the middle of the wing disc • You could then hypothesize that Dpp released here diffuses in both directions to form a gradient which could turn on multiple genes in a concentration- dependant manner The next question to ask would be whether or not there is are multiple target genes for the Dpp ligand in these surrounding cells • There are 2 such target genes: one called spalt, with a narrow expression domain (shown in brown), and the other is omb (shown in blue) • Spalt is found only in the center of the wing disc, while omb is found in a wider radius • You could argue that higher concentrations of Dpp turn on spalt, while lower concentrations of Dpp are able to turn on Omb They then made Dpp mutant flies to see whether or not spalt and omb are actually targets of Dpp, which indeed they are • Looking at the null mutant, you can see no more coloring for splalt and omb once Dpp isn’t there anymore • This shows that Dpp is necessary for splalt and omb expression (but not sufficient) To check if Dpp is sufficient for spalt/omb expression you then overexpress Dpp in some wing discs where Dpp is not normally expressed • Indeed, spalt and omb are expressed wherever Dpp is expressed in the mutant;
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