Transcriptional Control of the Development of Central Serotonergic Neurons

The central serotonergic neurons [5-hydroxytryptamine (5-HT) neurons] are several clusters of neurons located bilaterally along the midline and in the adjacent reticular formation of the brainstem. These neurons project widely to almost every part of the brain and spinal cord, and thereby modulate a variety of developmental processes and animal behaviors. A deregulation of the 5-HT level in the central nervous system might contribute to numerous psychiatric disorders, including fear, aggression, depression, and anxiety, and to pain modulation. The recent identification of 5-HT-specific transcription factors and the genetic manipulation of these factors in mice have begun to unveil molecular mechanisms underlying the specification, differentiation, survival, and maintenance of the central 5-HT neurons. This chapter summarizes some of recent advances about transcriptional control of 5-HT neuron development, and highlights the results from gene-targeting experiments in mice. The discussion concentrates on two classes of transcription factors. One class, represented by Nkx2.2 and Mash1, is expressed in 5-HT progenitor cells residing within the ventricular zone. The second class, represented by Lmx1b and Pet1, is expressed in 5-HT postmitotic neurons only. The comparison of different mutant lines that lack an individual transcription factor has permitted us to speculate about their relationship during the development of 5-HT neurons. Finally, behavioral study of knockout mice with impaired 5-HT systems have shown the involvement of some transcription factors in the etiology of psychiatric abnormalities.