The neurotransmitter serotonin has been suggested to function in morphogenesis, before the appearance of neurons. Fukumoto et al. tested this putative function in the early development of two vertebrate species, the frog and the chick. The authors screened various drug inhibitors of the serotonin signaling pathway in frog embryos at early stages after fertilization. They discovered that inhibitors of the R3 and R4 subtypes of serotonin receptor, as well as an inhibitor of monoamine oxidase (MAO), an enzyme that degrades serotonin, blocked asymmetric left-right patterning. The phenotype included anomalous placement of organs such as the heart, gut, and gall bladder. A drug that blocks serotonin synthesis did not cause organ randomization, which suggests that endogenous serotonin is of maternal origin and is present prior to neurogenesis. Expression of known asymmetrically transcribed genes, including XNR-1 and Xlefty, was also altered, which indicates that serotonin signaling functions upstream of asymmetric gene expression. After fertilization, serotonin expression was localized to cells descendant of the right central blastomere and decreased during development. Thus, serotonin expression is asymmetric along the left-right axis at very early development stages. Microinjection of either an R3 antagonist or amine-binding protein, which binds serotonin and blocks its signaling, into the right ventral blastomere of a four-cell-stage embryo blocked asymmetric development. In contrast, injection of either agent into the left dorsal blastomere had little effect, indicating that serotonin signaling already exists by the four-cell stage. Unlike the frog, chick embryos revealed an increase of serotonin expression in early embryogenesis. However, inhibition of MAO also blocked left-right asymmetry during development. The enzyme may regulate the availability of serotonin spatially in the early developing chick but temporally in the frog.
T. Fukumoto, I. P. Kema, M. Levin, Serotonin signaling is a very early step in patterning of the left-right axis in chick and frog embryos. Curr. Biol. 15, 794-803 (2005). [PubMed]