Rapid nuclear responses to target-derived neurotrophins require retrogradetransport of ligand-receptor complex

Target-derived neurotrophins initiate signals that begin at nerve terminals and cross long distances to reach the cell bodies and regulate gene expres sion. Neurotrophin receptors, Trks, themselves serve as retrograde signal c arriers. However, it is not yet known whether the retrograde propagation of Trk activation reflects movement of Trk receptors from neurites to cell bo dies or reflects serial activation of stationary Trk molecules. Here, we sh ow that neurotrophins selectively applied to distal neurites of sensory neu rons rapidly induce phosphorylation of the transcription factor cAMP respon se element-binding protein (CREB) and also cause a slower increase in Fos p rotein expression. Both nuclear responses require activation of neurotrophi n receptors (Trks) at distal nerve endings and retrograde propagation of Tr k activation to the nerve cell bodies. Using photobleach and recovery techn iques to follow biologically active, green fluorescent protein (GFP)-tagged BDNF receptors (TrkB-GFP) in live cells during retrograde signaling, we sh ow that TrkB-GFP moves rapidly from neurites to the cell bodies. This rapid movement requires ligand binding, Trk kinase activity, and intact axonal m icrotubules. When they reach the cell bodies, the activated TrkB receptors are in a complex with ligand. Thus, the retrograde propagation of activated TrkB from neurites to cell bodies, although rapid, reflects microtubule-de pendent transport of phosphorylated Trk-ligand complexes. Moreover, the rel ocation of activated Trk receptors from nerve endings to cell bodies is req uired for nuclear signaling responses. Together, these data support a model of retrograde signaling whereby rapid vesicular transport of ligand-recept or complex from the neurites to the cell bodies mediates the nuclear respon ses.