The chapter walks through lesion experiments showing that the yak-derived RETSAT variant lets mice repair demyelinated brain lesions that otherwise stay damaged under hypoxia, unlike controls. The hosts then trace a surprising follow-up finding: expressing RETSAT only in oligodendrocyte precursor cells fails to trigger repair, but expressing it only in neurons restores remyelination, indicating neurons send a signal that tells the precursor cells to mature and rebuild myelin.
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The lesion model used LPC-induced demyelination created by micro-injecting a toxin into the brain, imaged as a hole in myelin staining that persisted in controls but closed within about 14 to 15 days when RETSAT was present.
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Restricting the RETSAT gene to oligodendrocyte precursor cells alone produced no repair, ruling out a direct mechanism inside those cells despite them being the cells that ultimately form new myelin.
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The hosts frame the finding as evidence that the original problem was a breakdown in signaling to already-present precursor cells rather than an absence of the cells themselves.
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1:02:43>> but from what I've previously told you that has to do with these oligodendritty right and the pregentor cells those stem cells becoming oligodendrites >> OPC's >> oh the OPC's yeah becoming the myelin sheets >> yes >> does the retat have something to do with that pathway >> right cuz >> that's that's what I love about this it's like very gradually I was just following the figures in the main text and they're telling a story of like first we established red stat has something to do with myelin survival in hypoxia. Now does it have something to do with repairing the myelin specifically and that's where we get into these lesion studies. What you can
1:03:23do is you can have LPC induced demethylation. Basically you take like a kind of poison and you micro inject it into parts of the brain. And so you see like um in the top row there's like a hole. Yes. In the green the green is is tagging the myelin and you you've created like kind of a hole, right? Um on the bottom row there's no hole. >> Mhm. >> The top row is the control. The hole cannot be repaired. But on the bottom row because of the red stat the hole was repaired. This is basically I think this was um 15 days 14 days after the initial injury. So they've done some kind of injury and you're seeing that that injury is persisting in the control
1:04:04under hypoxia but >> in the red stat right so now now now now we're on to it because this is this is different that what we're pointing to here specifically is the ability to uh for the the regenerative once you've created a uh this problem >> yeah the lesion this is and this is like simulating what MS would do >> would do you're actually doing the thing that MS doesn't do which is the OPC's go through their pathway to then become the algalaentric sites that can now rem uh remlanate. >> Yeah. >> And it's not happening in the control which is what we would see in an MS patient but when we have the reset it is
1:04:45happening. And now we've made the connection not only to the hypoxia environment but specifically to this idea that the stem cell can get to its adult maturity and redo the repair process that we're actually trying to target starting from this evolutionary uh inspiration. >> Exactly. And so we're getting down to the mechanism, >> but we're still not there yet. Okay. >> Right. Because so far what what have we established? We've established that this new gene that's in Yaks, it can reminate lesions. How is it doing it though? Right now, we get into the process. This is the detective work. We're digging deeper and deeper into now trying to understand what is the exact molecular
1:05:27pathway that is going to get us there because that is how we get a therapy. Right. >> Right. We're not going to get a therapy by like genetically modifying patients. That's not what we're doing. >> We're trying to figure out what is the gene doing, >> right? And can we maybe hijack that pathway? >> Yes. >> Right. >> Yes. >> Okay. So, let's move on. And this is where we get into a weird weird discovery. >> Okay.
Evolutionary BiologyNeurobiologyPharmacologyRegenerative Medicine