Neuropeptides control life-phase transitions.

The growth toward adulthood occurs mainly through one or several intermediate stages or larval forms. Driven by environmental and internal state cues, all animals undergo one or more transitions during their life, which are accompanied by changes in morphology, physiology, and behavior. Larval settlement in the annelid Platynereis dumerilii is a prime example of such a life-phase transition. In PNAS, Conzelmann et al. (1) show that larval settlement is under the control of a myoinhibitory neuropeptide (MIP) produced by neurosecretory cells in the animal’s brain. Platynereis is an emergingmodel organism for the study of animal development and behavior. This marine annelid worm belongs to the Lophotrochozoa, the third major branch of bilaterian animals next to Ecdysozoa (insects and nematode worms) and Chordata (lancelets, tunicates, and vertebrates). Genome investigation revealed that the genes of Platynereis are more closely related to those of vertebrates than to those of insects or nematodes. The urbilaterian ancestor of protostomes and deuterostomes likely had complex, intron-rich genes that are still present in Platynereis and human, but have been lost in insect and nematode genomes (2). The CNS of Platynereis shares a complex molecular architecture with that of vertebrates, implying that the urbilaterian ancestor also possessed a well-developed CNS (3). Platynereis has retained ancient sensorymotor circuits with low levels of integration, as well as combined sensory-neurosecretory cell types that are also found in the vertebrate forebrain (4, 5). In addition, the sensory-associative centers in the annelid brain, known as the mushroom bodies, show deep homology with the vertebrate cortex, which indicates that the origin of higher brain centers also dates back to prebilaterian times (6). Platynereis larvae swim for several days as plankton, change shape twice, and then turn into large segmented worms. Larval settlement is the process by which the planktonic larva stops swimming, explores, attaches to a substrate, and begins its benthic life (7). The transition to a next life-cycle stage is a dynamic event. Larvae can reject one site and select another for settlement. Such active site selection is often mediated by environmental cues. Although a variety of chemicals, including proteins, free fatty acids, polysaccharides, inorganic ions, and neurotransmitters, have been proposed as inducers of larval settlement in marine annelid worms, no internal regulator had so far been identified. The most diverse class of signaling molecules in the CNS are neuropeptides, short sequences of amino acids that act through binding and activation of G protein-coupled receptors (8). By operating as hormones, neurotransmitters, or neuromodulators, neuropeptides are involved in many biological processes, such as reproduction, metabolism, feeding, circadian rhythms, sensorimotor integration, adaptive behaviors, and cognition. It has become clear that many neuropeptidergic systems have been conserved throughout the animal kingdom (9). Like the larvae of most marine invertebrates, Platynereis larvae swim with the help of a band of cilia. The ciliated cells are innervated by axons from neuropeptide-containing neurons in the CNS. Conzelmann et al. exposed swimming larvae to various synthetic neuropeptides and found that they influenced ciliary swimming (10). The evolutionarily conserved MIP neuropeptide is of particular interest because it triggered the arrest of ciliary beating and induced exploratory crawling behavior on the substrate, two features typical for larval settlement behavior. Exposure to MIP did not induce larval settlement of swimming larvae in which the MIP receptor was knocked down by a specific morpholino oligonucleotide, which sterically blocks mRNA translation upon binding to MIP receptor transcripts. Conzelmann et al. (1) conclude that exposure to MIP bypasses the chemical environmental cues responsible for the timing of larval settlement, and that MIP triggers a behavioral program for larval settlement by functionally activating its G proteincoupled receptor expressed in cells adjacent to MIP-containing cells. MIP neuropeptides are characterized by a W-X6–8-Wamide motif (11). In Platynereis, the last but not the first tryptophan (W) residue is crucial for MIP receptor activation and hence induction of larval settlement. The first MIP neuropeptide was identified in 1991 in the locust Locusta migratoria and was found to inhibit muscle contractions in vitro (12). MIPs (also named allatostatin B and prothoracicostatin) belong