The evolutionary origins of antagonistic neurotrophin signaling

1223 The Rockefeller University Press $30.00 J. Cell Biol. Vol. 216 No. 5 1223–1225 https://doi.org/10.1083/jcb.201702115 Seminal work from Viktor Hamburger and Rita Levi-Montalcini established a major tenant of our modern understanding of nervous system development: the neurotrophic factor hypothesis (Hamburger and Levi-Montalcini, 1949). The findings and implications of this hypothesis include the following. (a) Neurons are produced in excess, and a percentage are eliminated over development. We now know that this overproduction and refinement is a common design principle of many nervous system components, including synapses and axons. (b) Neurotrophic (neuron nourishing) factors emanate from targets like the muscle and skin, which are required for neuron survival. If a target is removed or added, excess death or survival is observed, respectively. Stanley Cohen worked with Levi-Montalcini to purify NGF, the first of four neurotrophin family ligands discovered in vertebrates (Cohen, 1960). (c) Implicit within these findings is the notion of competition for construction/destruction decisions (e.g., survival/death, axon growth/degeneration, and synapse stabilization/restriction). We now appreciate that the decision to survive or die can often times be represented by two antagonistic signaling pathways. For example, in vertebrate sympathetic neurons, target-derived NGF binds an axonal receptor tyrosine kinase, TrkA, to mediate constructive events, whereas the tumor necrosis factor receptor (TNFR) family member p75NTR mediates destructive events. Importantly, p75NTR promiscuously binds all neurotrophins or can bind proneurotrophins using VPS10 family members like sortilin or Sorcs2 as coreceptors (Lee et al., 2001; Majdan et al., 2001; Nykjaer et al., 2004). Although the molecular logic for how antagonistic constructive and destructive signaling pathways tune the number of axons, synapses, and neurons is becoming established for vertebrates, the evolutionary history of these pathways is less clear. A combination of bioinformatic and experimental analyses revealed a single Trk receptor and neurotrophin ligand in both the lancelet Amphioxus and the snail Aplasia (BenitoGutiérrez et al., 2005; Kassabov et al., 2013). In 2008, Zhu et al. (2008) suggested that Drosophila melanogaster also encodes the neurotrophin ligands Drosophila neurotrophin 1 (DNT1), DNT2, and Spätzle (Spz). As might be expected, these are more distantly related to vertebrate neurotrophins than those identified in Amphioxus or Aplasia, but they retain a cystine knot that is characteristic of the neurotrophins, as evidenced further in this issue by Foldi et al. with new structural modeling. Moreover, these putative Drosophila neurotrophins are required for motor neuron survival and axon growth (Zhu et al., 2008). Importantly, there are no Trk receptor homologues in Drosophila, which has led some to argue that DNT1, DNT2, and Spz are not bona fide neurotrophin orthologues (Kassabov et al., 2013). If not Trk, what are the receptors that these DNTs use to promote the apparent neurotrophin-like activity? A follow-up study by McIlroy et al. (2013) elegantly showed that instead of Trk receptors, DNT1 and 2 display physical and genetic interactions between the Toll-6 and -7 to promote cell survival. Notably, although Toll receptors are widely regarded as being involved in innate immunity, the first Toll phenotype discovered was developmental. Indeed, Toll mutant Drosophila larvae produced an underdeveloped ventral portion so profound that when discovered, Christiane Nüsslein-Volhard exclaimed, “Das war ja toll! ” (meaning, “That was great! ”), leading to the receptor’s naming. Although DNTs acting through Toll receptors explain constructive neurotrophin signaling, an explanation for destructive proor mature neurotrophin signaling was unknown until now. In this issue, Foldi et al. (2017) suggest that like survival and axon growth signaling, death signaling is also mediated by DNTs and Toll receptors. They describe a three-tier hierarchy capable of interpreting survival versus death decisions through DNT–Toll signaling.