maxschelski.bsky.social
Neuroscientist. Developing mathematical models of cell biology. Coding Python. Imaging neurons. #NeuroDev #Microtubules
Going to model cell biology of synaptic plasticity in upcoming PostDoc.
PhD Student in Bradke Lab.
https://github.com/maxschelski/
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Thanks for the question, Andreas! I published this end of 2022 with Frank Bradke as a two-author paper in Science Advances: www.science.org/doi/10.1126/.... Happy to talk about any result or question any time. :)
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Awesome - thanks a lot for compiling! I had missed a few people from the list. If possible, could you add me to the list as well? I'm looking at the role of microtubules in neurodevelopment - combining imaging of neurons (live-cell imaging and stainings) with biophysical models.
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However, faster MT-RF reduces MT mass noticeably (see graph). Therefore, slowdown of MT-RF in the axon would increase MT mass (which is also what I see in my biophysical model). I would suspect that slowdown of MT-RF could indirectly increase the number of mitochondria in the axon.
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We don't know for sure. But mitochondria can be transported much more quickly (15 µm/min when they are not stationary to my knowledge) than microtubules flow retrogradely (0.5 µm/min). Therefore I suspect that there is no big direct effect of microtubule retrograde flow on mitochondria movement.
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In short, at this point we don't know which mechanism(s) could slow down MT-RF in the axon. It's one of the very intriguing follow-up questions. Thanks for asking! :)
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This could suggest that modifications of the MT array could slow down MT-RF. But even actin could be involved. Actin is at least important to keep the MT array together for homogenous retrograde flow. Depolymerizing actin (LatA) leads to MTs that quickly move both retrogradely and anterogradely.
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What slows down microtubule retrograde flow (MT-RF) in the axon is an even more open question. It could be the change in MT orientation in the axon - too few microtubules with their plus-ends to the soma. However, I also saw that Taxol slows down MT-RF before changing MT orientation (right side).
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To make matters even more interesting, I also see that inhibiting Myosin II slows down MT-RF (in the middle). This could indicate that Myosin might also somehow be involved in driving MT-RF.
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However, I also recruited two different Kinesin motor domains to the plasma membrane. For both motor domains I saw something like faster MT-RF - with a delay after recruiting them to the membrane. I would say, the jury is still out on whether Dynein or Kinesins drive MT-RF physiologically.
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This would suggest that Dynein could speed up MT-RF through microtubules that have their plus-end towards the soma. One result supporting this, is that recruiting Dynein to the plasma membrane speeds up MT-RF in dendrites (50% plus-ends to soma) but not in axons (2% plus-ends to soma).
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I also found that recruiting endogous Dynein or an overexpressed Dynein motor domain is sufficient to speed up MT-RF. Recruting a motor deficient point mutant had no effect (see video). I saw the same also for the overexpressed minus-end directed motor domain of KIFC1.
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I found that acute or chronic inhibition of Dynein slows down MT-RF. This could suggest that Dynein might drive MT-RF in the cell.
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Thanks a lot, Manuel! What drives microtubule retrograde flow (MT-RF) physiologically is actually still an open question. At this moment, we don't know whether MT-RF is fueled by plus-end (Kinesins) or minus-end directed (e.g. Dynein) motors inside the cell.
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We called this process "microtubule retrograde flow" since it reminded us of an intracellular process of another part of the skeleton of the cell, actin, which is long known as "actin retrograde flow".
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I am very sorry for the confusion! I am only looking at a single cell/neuron here, specifically at a big network of polymers (the microtubule network) inside the cell, that acts as railroads for the neuron. We found that this big network is moving backwards as a whole inside the cell.
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Or developing #oligodendrocytes? Might microtubule retrograde flow be relevant to other cells with microtubule-filled, dynamic processes? So far, we only looked at central nervous system neurons: www.science.org/doi/10.1126/...
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Thanks a lot. :)