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The Journal of Neuroscience, November 5, 2003, 23(31):9961-9967

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Development/Plasticity/Repair
Lmx1b, Pet-1, and Nkx2.2 Coordinately Specify Serotonergic Neurotransmitter Phenotype

Leping Cheng,1,2 * Chih-Li Chen,1,2 * Ping Luo,1,2 Min Tan,3 Mengsheng Qiu,3 Randy Johnson,4 and Qiufu Ma1,2

1The Dana-Farber Cancer Institute, 2Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, 3Department of Anatomical Sciences and Neurobiology, School of Medicine, University of Louisville, Louisville, Kentucky 40292, and 4Program in Genes and Development, Department of Biochemistry and Molecular Biology, University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030

Serotonergic (5-HT) neurons in the brainstem modulate a wide range of physiological processes and behaviors. Two transcription factor genes, Pet-1 and Nkx2.2, are necessary but not sufficient to specify the 5-HT transmitter phenotype. Here we show that the Lim class homeobox gene Lmx1b is 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 in Lmx1b null 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 of Lmx1b plus Pet-1 is able to induce formation of 5-HT cells in the most ventral spinal cord, where Nkx2.2 is normally expressed. Combined expression of all three genes, Lmx1b, Pet-1, and Nkx2.2, 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.

Key words: Lmx1b; Pet-1; Nkx2.2; serotonergic; neurotransmitter specification; brainstem

Received July 18, 2003; revised August 27, 2003; accepted August 30, 2003.




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