Lmx1b, Pet-1, and Nkx2.2 coordinately specify serotonergic neurotransmitter phenotype.
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.
Cheng
Leping
L
The Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Chen
Chih-Li
CL
Luo
Ping
P
Tan
Min
M
Qiu
Mengsheng
M
Johnson
Randy
R
Ma
Qiufu
Q
D000818:Animals; D002642:Chick Embryo; D018274:Electroporation; D018507:Gene Expression Regulation, Developmental; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D017403:In Situ Hybridization; D060850:LIM-Homeodomain Proteins; D051379:Mice; D008817:Mice, Mutant Strains; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010641:Phenotype; D012249:Rhombencephalon / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins
C484684:Fev protein, mouse; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; C112149:LIM homeobox transcription factor 1 beta; D060850:LIM-Homeodomain Proteins; C000715627:Nkx2-2 protein, mouse; D014157:Transcription Factors; D029961:Zebrafish Proteins; C000715630:nkx2.2b protein, zebrafish; D012701:Serotonin