Serotonin transporter function is an early step in left-right patterning in chick and frog embryos.

The neurotransmitter serotonin has been shown to regulate a number of embryonic patterning events in addition to its crucial role in the nervous system. Here, we examine the role of two serotonin transporters, the plasma membrane serotonin transporter (SERT) and the vesicular monoamine transporter (VMAT), in embryonic left-right asymmetry. Pharmacological or genetic inhibitors of either SERT or VMAT specifically randomized the laterality of the heart and viscera in Xenopus embryos. This effect takes place during cleavage stages, and is upstream of the left-sided gene XNR-1. Targeted microinjection of an SERT-dominant negative construct confirmed the necessity for SERT function in embryonic laterality and revealed that the descendants of the right ventral blastomere are the most dependent upon SERT signaling in left-right patterning. Moreover, the importance of SERT and VMAT in laterality is conserved in chick embryos, being upstream of the early left-sided gene Shh. Endogenous transcripts of SERT and VMAT are expressed from the initiation of the primitive streak in chick and are asymmetrically expressed in Hensen's node. Taken together our data characterize two new right-sided markers in chick gastrulation, identify a novel, early component of the left-right pathway in two vertebrate species, and reveal a new biological role for serotonin transport.