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During recent years, neurotrophins have increasingly become a focus of neuroscience research. These proteins are crucial for neural development, but also contribute to the function of the adult brain, particularly with respect to neural plasticity. Two articles in this issue review different aspects of the mechanisms and functions of neurotrophin signalling.

On page 615, Zweifel, Kuruvilla and Ginty discuss how the signal that is initiated when a neurotrophin binds to its receptor — often far from the cell body, perhaps on a growth cone at the tip of a developing axon — is carried retrogradely to the cell body. There are several possible mechanisms for such retrograde signalling, including the formation of a 'signalling endosome' in which the neurotrophin–receptor complex is internalized and transported within the cell; retrograde spread of signalling effector molecules; waves of receptor activation travelling back along the cell membrane; and the propagation of calcium waves, initiating from the activated receptors. There is strong evidence for the signalling endosome model, although the authors concede that the other mechanisms might also be important.

Lu, Wang and Woo focus on a different aspect of neurotrophin function in their review on page 603. Neurotrophins are generated by the cleavage of precursors known as proneurotrophins, and it has recently become clear that proneurotrophins also have important biological functions in their own right. Indeed, these molecules often have effects that oppose those of mature neurotrophins, for example, promoting long-term depression rather than long-term potentiation. The cleavage of proneurotrophins to form neurotrophins therefore represents a crucial regulatory mechanism that not only modulates the activity of neurotrophins, but might also control the balance between the effects of proneurotrophins and neurotrophins.

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In this issue. Nat Rev Neurosci 6, 583 (2005). https://doi.org/10.1038/nrn1738

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