As tiny embryos in the womb, we start out with a lot more neuronal material than we actually need. During development, the body drastically prunes back the excess, cutting the branches from nerve cell bodies, known as axons, as well as entire neurons.
Scientists have long assumed that the decision whether to cull or keep an axon was coordinated by the axon itself, rather than by the cell body from which it extends. In recent years, tantalizing clues from several research groups have challenged that assumption. Now researchers at The Rockefeller University have proven that the cell body actively controls axon degeneration, and have uncovered many of the molecular details that allow this long-range communication.
In an article published February 18 in Cell, they report that the instructions telling axons in developing embryos whether to live or die come from the cell body, not the axon. “This is a surprising finding,” notes senior author Marc Tessier-Lavigne, President of Rockefeller University and the Carson Family Professor in the Laboratory of Brain Development and Repair. “When the axon senses a ‘distress signal’, a lack of a growth factor called NGF, it doesn’t make the decision to degenerate by itself. It actually sends the information to the cell body, which is quite far away, and the cell body sends its decision back down the axon.”
Axons in distress
The survival of some axons depends on the presence of NGF in their local environment, a sign that there are plenty of nutrients around. “Because NGF is present at the tips of axons, far from cell body, it has been hard for scientists to envision that the cell body played a central role in axon degeneration,” says co-first author David Simon, a postdoctoral fellow in the lab of Tessier-Lavigne. “And indeed, our study confirmed that all the cellular machinery that is needed to die is present in axon. However the axon needs the message from the cell body to know when to degenerate.”
Tessier-Lavigne, Simon, co-first author Jason Pitts, and their colleagues followed a fairly straightforward procedure. They severed the connection between axons and the cell body in mouse neurons. When they removed NGF to mimic the distress signal that normally informs neurons that an axon should degenerate, they saw that only axons that remained connected to their cell bodies would do so. “When axons have been isolated from their cell body, the internal cell process that normally leads to their degeneration won’t turn on,” says Simon.
Looking closer, the researchers saw that when NGF levels fall, the cell body activates a gene that makes a protein known as Puma, which is associated with cell death and is present in the cell body. They suspect that once Puma gets activated, it triggers a message within the cell that ultimately instructs the axon to die.
A fail-safe mechanism
The idea that the cell body coordinates the degeneration signal in axons may be new to neuroscientists, but it does make biological sense, the researchers note. While axons only detect signals in their immediate environment, the cell body receives multiple cues about growth conditions from different directions. For instance, the Cell experiment used sensory neurons that convey pain in the skin’s surface, where NGF levels can fluctuate periodically. “Our findings show the axon won’t make the decision to die based on an immediate lack of NGF,” Simon says. By leaving the decision up to the cell body, the neuron has a “fail safe” that prevents it from degenerating unnecessarily, the researchers propose.
The findings have potential implications for researchers studying certain conditions in which axons degenerate excessively, the authors note. In some neurodegenerative diseases, the affected neurons adopt some of the same pathways that drive axon pruning during normal embryonic development. The new findings suggest that some of these diseases may be caused by problems in signaling from the cell body, which keeps mistakenly green-lighting axon degeneration.
“If researchers could find a way to interfere with the expression or function of Puma, that could be very neuroprotective, and potentially protect neurons from degenerating,” says Simon.
About this neuroscience research
Source: Katherine Fenz – Rockefeller University Image Credit: The image is credited to Laboratory of Brain Development and Repair at The Rockefeller University/Cell. Original Research:Abstract for “Axon Degeneration Gated by Retrograde Activation of Somatic Pro-apoptotic Signaling” by David J. Simon, Jason Pitts, Nicholas T. Hertz, Jing Yang, Yuya Yamagishi, Olav Olsen, Milica Tešić Mark, Henrik Molina, Marc Tessier-Lavigne in Cell. Published online February 18 2016 doi:10.1016/j.cell.2016.01.032
Axon Degeneration Gated by Retrograde Activation of Somatic Pro-apoptotic Signaling
Highlights •The cell body is an active and essential regulator of distal axon degeneration •The cell body integrates retrograde loss of Akt and gain of JNK signaling •Pro-apoptotic Puma in the cell body initiates an anterograde degenerative program
Summary During development, sensory axons compete for limiting neurotrophic support, and local neurotrophin insufficiency triggers caspase-dependent axon degeneration. The signaling driving axon degeneration upon local deprivation is proposed to reside within axons. Our results instead support a model in which, despite the apoptotic machinery being present in axons, the cell body is an active participant in gating axonal caspase activation and axon degeneration. Loss of trophic support in axons initiates retrograde activation of a somatic pro-apoptotic pathway, which, in turn, is required for distal axon degeneration via an anterograde pro-degenerative factor. At a molecular level, the cell body is the convergence point of two signaling pathways whose integrated action drives upregulation of pro-apoptotic Puma, which, unexpectedly, is confined to the cell body. Puma then overcomes inhibition by pro-survival Bcl-xL and Bcl-w and initiates the anterograde pro-degenerative program, highlighting the role of the cell body as an arbiter of large-scale axon removal.
“Axon Degeneration Gated by Retrograde Activation of Somatic Pro-apoptotic Signaling” by David J. Simon, Jason Pitts, Nicholas T. Hertz, Jing Yang, Yuya Yamagishi, Olav Olsen, Milica Tešić Mark, Henrik Molina, Marc Tessier-Lavigne in Cell. Published online February 18 2016 doi:10.1016/j.cell.2016.01.032