Throughout development, axons navigate long distances to find their ultimate synaptic partners. As it approaches its proper target, the axon often finds survival signals that stave off apoptosis. These signals must somehow be conveyed all the way back to the cell body. The new findings unveil a potential general mechanism for such survival signaling: local translation and retrograde transport of transcription factors.
Cox et al. were originally interested in identifying those mRNAs that are translated in axons, which contain ribosomal machinery that synthesizes signaling proteins and cytoskeletal regulators. In their search, says Jaffrey, “we found something strange, which in many ways had already been discovered about ten years ago.”
That oddity was mRNA for a transcription factor called CREB, which turns on antiapoptotic genes when neurons sense the NGF survival factor. The axonal CREB pool was translated when axons were given NGF, although how the local translation pathway is controlled is not known.
A decade ago, CREB was also found in dendrites. Getting at its function there was difficult, but the extra length of axons made it possible to examine its axonal role. The authors applied CREB siRNAs selectively to axons to inhibit its translation there. Without this pool of CREB, neurons no longer survived when their axons encountered NGF.
In untreated axons, NGF-induced CREB was seen traveling back toward the cell body along with motor-driven endosomes carrying NGF's receptor and the kinases it activates. The transported CREB sported a phosphate modification known to help it turn on prosurvival genes.
“CREB from axons is different from the nuclear pool,” says Jaffrey. “It may undergo axon-specific modifications—phosphorylation, sumoylation, or association with binding proteins—that endow it with specific transcriptional abilities.”