Roles of Retinoic Acid Signaling in Shaping the Neuronal Architecture of the Developing Amphioxus Nervous System

The morphogen retinoic acid (RA) patterns vertebrate nervous systems and drives neurogenesis, but how these functions evolved remains elusive. Here, we show that RA signaling plays stage- and tissue-specific roles during the formation of neural cell populations with serotonin, dopamine, and GABA neurotransmitter phenotypes in amphioxus, a proxy for the ancestral chordate. Our data suggest that RA signaling restricts the specification of dopamine-containing cells in the ectoderm and of GABA neurons in the neural tube, probably by regulating Hox1 and Hox3 gene expression, respectively. The two Hox genes thus appear to serve distinct functions rather than to participate in a combinatorial Hox code. We were further able to correlate the RA signaling-dependent mispatterning of hindbrain GABA neurons with concomitant motor impairments. Taken together, these data provide new insights into how RA signaling and Hox genes contribute to nervous system as well as to motor control development in amphioxus and hence shed light on the evolution of these functions within vertebrates.