Conveying signals from the tips of axons to the nucleus: Axon-derived transcription factors

During the development of the nervous system, neurons extend axons that navigate through various tissues to innervate their specific synaptic targets.  Many critical processes that occur during neuronal development, such as axonal elongation, pathfinding, axonal branching, and synaptogenesis are regulated by signaling molecules in the extracellular environment that act on growth cones at the tips of developing axons.  In many cases, these signals induce the activation of pathways that are limited to growth cones.  However, in some cases, signaling at the growth cone subsequently results in the regulation of gene expression in the nucleus.  This long-distance communication indicates that a signal is retrogradely conveyed along the axon, from the growth cone to the soma.  However, the nature of these retrograde signals and the mechanisms by which they regulate transcription are largely unknown.  

How are these signals conveyed from the axons to the nucleus?  An unusual feature of this type of signaling is that the signal must be conveyed from the ends of axons to the nucleus, which can range from millimeters to tens of centimeters.

We have explored retrograde signaling induced by nerve growth factor (NGF).  NGF is a signaling molecule that acts on axons to regulate transcription in the nucleus.  NGF is made by target tissues such as skin.  During development, as the axons of sensory neurons elongate and arrive at their targets, they sense NGF and convey a retrograde signal that promotes neuronal survival.  Axons that fail to reach their targets do not detect NGF, and die. 

Figure 1. Local translation and retrograde transport of CREB mediates neuronal survival. (i) NGF binds and activates TrkA receptors. (ii) TrkA activation leads to translation of axonal CREB mRNA and (iii) the production of CREB protein. NGF-bound, activated TrkA receptors are internalized into endosomes and axonally translated CREB protein associates with this NGF-pTrkA signaling endosome, which is required for downstream activation of CREB signaling in the cell body. (iv) CREB is retrogradely transported to the nucleus. (v) Axonally-derived pCREB initiates the transcription leading to neuronal cell survival.


We have identified a novel mechanism by which signals at the growth cone can result in long distance signaling to the nucleus.  NGF signaling at axons activates a pathway that leads to CREB-mediated transcription and neuronal survival.  We found that this pathway is protein synthesis-dependent.  We made a cDNA library from distal axons and found that CREB mRNA, but not other transcription factor mRNAs, is localized to axons of DRG neurons and translated in response to NGF signaling.  The locally-synthesized CREB is retrogradely trafficked to the nucleus where it binds to CRE-containing promoters.  This axon-derived CREB is required for the increase in CRE-dependent transcription seen upon stimulation of distal axons with NGF.  Furthermore, neuronal survival elicited by NGF signaling at distal axons requires axon-derived CREB.  Our findings indicate that the retrograde survival signal generated upon axonal application of NGF includes the axonal synthesis of CREB.  This constitutes a novel retrograde signaling mechanism, whereby signaling events at the growth cone contribute to the transcriptional responses of the neuron via the local translation and retrograde trafficking of transcription factors from axon growth cones to the neuronal nucleus.

We are currently screening axons for the presence of novel axonal transcription factor mRNAs.  Our studies indicate that specific transcription factor mRNAs, as well as other mRNAs that encode other transcriptional regulators, are present in axons.  We are exploring the roles of these mRNAs in processes such as axonal guidance, neuronal differentiation, axonal branching, and synaptogenesis.