Local Synthesis for Retrograde Signaling

Science Signaling  17 Apr 2012:
Vol. 5, Issue 220, pp. ec109
DOI: 10.1126/scisignal.2003139

As neurons extend projections, such as axons, toward their targets, they receive signals from the targets. The sensory nerves of the trigeminal ganglia that innervate the face serve as a useful system to study both axonal targeting and neuronal fate specification (see Takatoh and Wang). Ji and Jaffrey isolated embryonic rat trigeminal ganglia neurons and cultured them in specialized chambers that enabled analysis of the axons separately from the cell bodies. Axonal application of bone morphogenetic protein 4 (BMP4), which is produced by the target epithelium of the maxillary and ophthalmic, but not the mandibular, regions of the face, produced an increase in the abundance of nuclear phosphorylated SMAD1, 5, and 8 (known targets of BMP4 signaling) and induction of a BMP4 target gene, Tbx3. This BMP4 response was prevented by inhibition of retrograde signaling by blocking the activity of the molecular motor protein dynein in the axons or by application to the cell body of an inhibitor of the BMP4 receptor, suggesting that retrograde transport of BMP4 and its receptor contributed to this SMAD signal in the cell body. Retrograde signaling, but not retrograde transport of BMP4, was blocked by application of protein synthesis inhibitors to the axons, suggesting that axonally localized translation contributed to the BMP4 signal. Transcripts encoding SMAD1, 5, and 8 were detected in the axons of the isolated neurons and in the axons of all trigeminal neurons in embryonic rats; however, in vivo the proteins were only detected in the axons innervating the ophthalmic and maxillary regions and not in those for the mandibular region. Brain-derived neurotrophin factor (BDNF) is a specific factor produced by the ophthalmic and maxillary target epithelium, and application of BDNF to the axons of the cultured neurons stimulated the synthesis of SMAD1, 5, and 8. By pretreating the cultured neurons with neurotrophin-free media, the authors showed that the BMP4 retrograde signal required both BDNF and BMP4 to produce an increase in nuclear phosphorylated SMADs in the cell body. The importance of BDNF for trigeminal nerve specification, but not axonal growth, was verified with mice genetically deficient in BDNF, which eliminated the differences in SMAD1, 5, and 8 abundance; nuclear phosphorylated SMADs; and Tbx3 abundance between the ophthalmic and maxillary nerves and the mandibular nerves. Thus, BDNF appears to prime the axons for receiving the BMP4 signal by stimulating the production of the SMADs in the axons to promote retrograde BMP4 signals.

S.-J. Ji, S. R. Jaffrey, Intra-axonal translation of SMAD1/5/8 mediates retrograde regulation of trigeminal ganglia subtype specification. Neuron 74, 95–107 (2012). [Online Journal]

J. Takatoh, F. Wang, Axonally translated SMADs link up BDNF and retrograde BMP signaling. Neuron 74, 3–5 (2012). [Online Journal]