Lmx1b, Pet-1, andNkx2.2Coordinately Specify Serotonergic Neurotransmitter Phenotype

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Abstract
Serotonergic (5-HT) neurons in the brainstem modulate a wide range of physiological processes and behaviors. Two transcription factor genes,Pet-1andNkx2.2, are necessary but not sufficient to specify the 5-HT transmitter phenotype. Here we show that the Lim class homeobox geneLmx1bis required for proper formation of the entire 5-HT system in the hindbrain, as indicated by the loss of expression of genes necessary for serotonin synthesis and transport inLmx1bnull mice. Lmx1b and Pet1 act downstream of Nkx2.2, and their expression is independently regulated at the time when 5-HT transmitter phenotype is specified. Ectopic expression ofLmx1bplusPet-1is able to induce formation of 5-HT cells in the most ventral spinal cord, whereNkx2.2is normally expressed. Combined expression of all three genes,Lmx1b, Pet-1, andNkx2.2, drives 5-HT differentiation in the dorsal spinal cord. Our studies therefore define a molecular pathway necessary and sufficient to specify the serotonergic neurotransmitter phenotype.