MCDB 423 Lecture 12: Lecture 12

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University of Michigan - Ann Arbor
Molecular, Cellular and Developmental Biology
MCDB 423
John Kuwada

Lecture 12 Slide 1 How might you probe this question? What does the virus do? -Does the virus have the ability to infect neural stem cells? (Could take a virus and use a mouse model and see where the mouse goes and what cells it infects, can do it with IPS cells, etc. and this is the case that neural cells are susceptible to the virus) -Does the virus inhibit notch signaling? You can culture these IPS cells in a 3D matrix called matrigel and if you put it in the right conditions, you can form some higher ordered structures called organoid -This has some resemblance of the structure of the brain slide 2 Notch signaling is a signaling pathway often used for organizing this choice of stem cell vs differentiating cell These are linage cartoons of neurogentic divisions we talked about One common feature in all 3 is when the stem cell divides, it gives rise to two daughter cells -If differentiation occurs, one daughter cell takes on a different path from the mother cell This asymmetric cell division is due to notch signaling Slide 3 You have receptors and ligand expressed on cell surface -Delta = ligand and can stimulate a neighboring cell by binding to notch When you have more delta expressed in one cell, it turns on notch in the neighboring cell Slide 4 This is a higher resolution view of notch signaling All cells have the capacity to express notch and delta When delta binds to notch and activates the receptor, the intracellular domain of notch becomes cleaved and translocate to the nucleus -Binds to the promoters of genes to stimulate gene expression -Hes is a major target (also called suppressor Hureles (SuH) Delta expression is one of the things that can be regulated by notch -So if you stimulate notch signaling in a cell, this cell will turn off its expression of delta -That means it’s less likely to activate notch in it’s neighboring cell This is kind of a feed-forward affect Slide 5 This is also called lateral inhibition Tip the balance; cause one cell to signal notch a little less well and express more delta -It’s a way to drive a choice between two neighboring cells -Cells needs to be neighbors Slide 6 Notch and delta were discovered by having too many neuroblasts Another mutant called numb has no neuroblast -Thus no sensory neurons slide 7 A lot of drosophila work leads to this understanding of what numb does Numb encodes a protein that inhibits the function of notch So the first thing you can do when you have two mutants, you can put them together to make a double mutant -This is called a genetic epistasis test -It’s a way to figure out the relationship between these two genes When they put numb and notch mutants together, there were too many sensory neurons They could also overexpress the expression of numb -What they got was too many sensory neurons This supports the model that numb is an inhibitor of notch If you don’t have notch, it doesn’t matter what was happe
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