The problem of pre-nervous neurotransmitter systems arose from studies carried out on different groups of invertebrates and vertebrates in the late 1950s to early 1960s. These investigations were motivated by an hypothesis formulated by K. S. Koshtoyants concerning the similarity between pre-nervous control processes and neuronal functions. Here, we review new data related to the embryogenetic and morphogenetic functions of serotonin (5-HT) and 5-HT-like substances in early embryos of sea urchins, mouse, and other species. Accumulating evidence across animal phyla indicates that 5-HT, together with other classical neurotransmitters, regulates basic developmental processes, including cell proliferation, migration, differentiation, and morphogenesis. Future investigations of cellular and molecular mechanisms underlying phylogenetically old functions of neurotransmitters could provide new insights into the evolutionary emergence of the vertebrate nervous system.

1. Classical neurotransmitters (such as acetylcholine, biogenic amines, and GABA) are functionally active throughout ontogenesis. 2. Based on accumulated evidence, reviewed herein, we present an hypothetical scheme describing developmental changes in this functional activity, from the stage of maturing oocytes through neuronal differentiation. This scheme reflects not only the spatio-temporal sequence of these changes, but also the genesis of neurotransmitter functions, from "protosynapses" in oocytes and cleaving embryos to the development of functional neuronal synapses. 3. Thus, it appears that neurotransmitters participate in various forms of intra- and intercellular signalling throughout all stages of ontogenesis.

Serotonin is a clinically important neurotransmitter regulating diverse aspects of cognitive function, sleep, mood, and appetite. Increasingly, it is becoming appreciated that serotonin signaling among non-neuronal cells is a novel patterning mechanism existing throughout diverse phyla. Here, we review the evidence implicating serotonergic signaling in embryonic morphogenesis, including gastrulation, craniofacial and bone patterning, and the generation of left-right asymmetry. We propose two models suggesting movement of neurotransmitter molecules as a novel mechanism for how bioelectrical events may couple to downstream signaling cascades and gene activation networks. The discovery of serotonin-dependent patterning events occurring long before the development of the nervous system opens exciting new avenues for future research in evolutionary, developmental, and clinical biology.

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Forty serotonin-related neurochemicals were tested on embryos and larvae of Lytechinus variegatus and other sea urchin species. Some of these substances (agonists of 5-HT1 receptors, antagonists of 5-HT2, 5-HT3 or 5-HT4 receptors, and inhibitors of the serotonin transporter, SERT) perturbed post-blastulation development, eliciting changes in embryonic/larval phenotypes typical for each class of receptor ligand. These developmental malformations were prevented completely or partially by serotonin (5-HT) or 5-HT analogs (5-HTQ, AA-5-HT), providing evidence for the putative localization of cellular targets. Immunoreactive 5-HT, 5-HT receptors and SERT were found in pre-nervous embryos and larvae of both L. variegatus and Strongylocentrotus droebachiensis. During gastrulation, these components of the serotonergic system were localized to the archenteron (primary gut), mesenchyme-like cells, and often the apical ectoderm. These results provide evidence that pre-nervous 5-HT may regulate early events of sea urchin embryogenesis, mediated by 5-HT receptors or the 5-HT transporter.