LAUSR

Abstract Neuropeptides are neurosecretory signaling molecules in protostomes and deuterostomes (together Nephrozoa). Little, however, is known about the neuropeptide complement of the sister group of Nephrozoa, the Xenacoelomorpha, which together form the Bilateria. Because members of the xenacoelomorph clades Xenoturbella, Nemertodermatida, and Acoela differ extensively in their central nervous system anatomy, the reconstruction of the xenacoelomorph and bilaterian neuropeptide complements may provide insights into the relationship between nervous system evolution and peptidergic signaling. Here, we analyzed transcriptomes of seven acoels, four nemertodermatids, and two Xenoturbella species using motif searches, similarity searches, mass spectrometry and phylogenetic analyses to characterize neuropeptide precursors and neuropeptide receptors. Our comparison of these repertoires with previously reported nephrozoan and cnidarian sequences shows that the majority of annotated neuropeptide GPCRs in cnidarians are not orthologs of specific bilaterian neuropeptide receptors, which suggests that most of the bilaterian neuropeptide systems evolved after the cnidarian–bilaterian evolutionary split. This expansion of more than 20 peptidergic systems in the stem leading to the Bilateria predates the evolution of complex nephrozoan organs and nervous system architectures. From this ancient set of neuropeptides, acoels show frequent losses that correlate with their divergent central nervous system anatomy. We furthermore detected the emergence of novel neuropeptides in xenacoelomorphs and their expansion along the nemertodermatid and acoel lineages, the two clades that evolved nervous system condensations. Together, our study provides fundamental insights into the early evolution of the bilaterian peptidergic systems, which will guide future functional and comparative studies of bilaterian nervous systems.