Abstract
Apoptotic cells expose Phosphatidylserine (PS), that serves as an “eat me” signal for engulfing cells. Previous studies have shown that PS also marks degenerating axonsduring developmental pruning or in response to insults (Wallerian degeneration), but the pathways that control PS exposure on degenerating axons are largely unknown. Here, we used a series of in vitro assays to systematically explore the regulation of PS exposure during axonal degeneration. Our results show that PS exposure is regulated by the upstream activators of axonal pruning and Wallerian degeneration. However, our investigation of signaling further downstream revealed divergence between axon degeneration and PS exposure. Importantly, elevation of the axonal energetic status hindered PS exposure, while inhibition of mitochondrial activity caused PS exposure, without degeneration. Overall, our results suggest that the levels of PS on the outer axonal membrane can be dissociated from the degeneration process and that the axonal energetic status plays a key role in the regulation of PS exposure.
Highlights
Axon elimination with or without the death of the cell body is a key feature in many neurological disorders and in response to nerve injury and chemical insults
We did not detect dextran staining within the axons for any of our treatments, supporting the conclusion that flagMFG-E8D89E staining in our studies identified solely extracellular PS (Figure S1G). These results demonstrate that PS is exposed on the external membrane of degenerating axons for all three in vitro models of axonal degeneration, suggesting it may be important for recognition of degenerating axons in both Wallerian degeneration and pruning
PS exposure is controlled by early activators of axonal degeneration pathways Since we detected PS exposure in all of our paradigms of axon degeneration, we aimed to identify the molecular mechanism that controls PS exposure in each one (Fig. 3a)
Summary
Axon elimination with or without the death of the cell body is a key feature in many neurological disorders and in response to nerve injury and chemical insults. Neurites are eliminated by pruning during development, a key process in the wiring of the nervous system[1,2]. Both during development and in response to insults, axons are eliminated through a discrete series of events that ends with the clearance of the remnants by glia or other engulfing cells[3]. Clearance of the debris is crucial for the recovery of the degenerated axon. When clearance does not occur properly, it can lead to tissue scarring and inflammation, preventing regeneration and causing developmental defects[3,4].
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