What neurons tell themselves: autocrine signals play essential roles in neuronal development and function

Highlights

• Activity-dependent autocrine signals play critical roles in synaptic plasticity.

• Transient retrograde signals can activate sustained autocrine signals.

• Drosophila is an ideal model system to investigate mechanisms of autocrine signaling.

Although retrograde neurotrophin signaling has provided an immensely influential paradigm for understanding growth factor signaling in the nervous system, recent studies indicate that growth factors also signal via cell-autonomous, or autocrine, mechanisms. Autocrine signals have been discovered in many neuronal contexts, providing insights into their regulation and function. The growing realization of the importance of cell-autonomous signaling stems from advances in both conditional genetic approaches and in sophisticated analyses of growth factor dynamics, which combine to enable rigorous in vivo dissection of signaling pathways. Here we review recent studies defining autocrine roles for growth factors such as BDNF, and classical morphogens, including Wnts and BMPs, in regulating neuronal development and plasticity. Collectively, these studies highlight an intimate relationship between activity-dependent autocrine signaling and synaptic plasticity, and further suggest a common principle for coordinating paracrine and autocrine signaling in the nervous system.

Introduction

Defining when and where extracellular signals are released is key to understanding how they direct neuronal structure and function. However, the broad expression profiles and pleiotropic phenotypes of evolutionarily-conserved signaling proteins has hindered a detailed view of their in vivo roles. Identifying the cellular requirement for a broadly-expressed secreted protein requires generating mosaic animals where the protein is deleted in only a few cells. Such conditional genetic approaches provide a critical test of signaling directionality in vivo, and have provided evidence for anterograde and retrograde pathways, and increasingly, autocrine pathways as well.

Cell-autonomy of signaling pathways in neurons is consistent with their established autocrine functions in non-neuronal tissues. In general, the extent to which secreted signals spread in vivo is controversial. For example, Wnt family members are palmitoylated and do not freely diffuse [1]. This lipid modification makes them highly hydrophobic and is proposed to promote local action of Wnt family members. Related concerns extend to members of the mammalian neurotrophin family. Brain-Derived Neurotrophic Factor (BDNF) is positively charged at physiological pH (pI > 9) [2], which is predicted to limit its diffusion by promoting electrostatic interactions between BDNF and proteins on the surface of the secreting cell, thus facilitating cell-autonomous signaling. Thus, the biochemical properties of signaling proteins are likely to facilitate highly local, autocrine signaling pathways.

Recent studies have revealed cell-autonomous functions for neurotrophins, including BDNF, as well as classical morphogens, such as Wnts and BMPs. These pathways play widespread roles in the developing and adult nervous system, and regulate processes from neuronal morphology to synaptic plasticity. The diverse contexts in which autocrine signals have been recently discovered begs the question of whether there is an underlying logic to their in vivo functions. Based on the studies reviewed here, we suggest two interrelated possibilities. The first is that the timing of activity-dependent autocrine signals may be particularly important at synapses where the rapid dynamics and highly focal action of an autocrine loop could enable tight coupling of synaptic activity to signal transduction. The second is that autocrine signals may often be activated in response to short-lived paracrine cues in order to sustain or amplify the initial intercellular cue.