Tlx3 and Tlx1 are post-mitotic selector genes determining glutamatergic over GABAergic cell fates.
Glutamatergic and GABAergic neurons mediate much of the excitatory and inhibitory neurotransmission, respectively, in the vertebrate nervous system. The process by which developing neurons select between these two cell fates is poorly understood. Here we show that the homeobox genes Tlx3 and Tlx1 determine excitatory over inhibitory cell fates in the mouse dorsal spinal cord. First, we found that Tlx3 was required for specification of, and expressed in, glutamatergic neurons. Both generic and region-specific glutamatergic markers, including VGLUT2 and the AMPA receptor Gria2, were absent in Tlx mutant dorsal horn. Second, spinal GABAergic markers were derepressed in Tlx mutants, including Pax2 that is necessary for GABAergic differentiation, Gad1/2 and Viaat that regulate GABA synthesis and transport, and the kainate receptors Grik2/3. Third, ectopic expression of Tlx3 was sufficient to suppress GABAergic differentiation and induce formation of glutamatergic neurons. Finally, excess GABA-mediated inhibition caused dysfunction of central respiratory circuits in Tlx3 mutant mice.
Cheng
Leping
L
The Dana-Farber Cancer Institute, and Department of Neurobiology, Harvard Medical School, 1 Jimmy Fund Way, Boston, Massachusetts 02115, USA.
Arata
Akiko
A
Mizuguchi
Rumiko
R
Qian
Ying
Y
Karunaratne
Asanka
A
Gray
Paul A
PA
Arata
Satoru
S
Shirasawa
Senji
S
Bouchard
Maxime
M
Luo
Ping
P
Chen
Chih-Li
CL
Busslinger
Meinrad
M
Goulding
Martyn
M
Onimaru
Hiroshi
H
Ma
Qiufu
Q
D026905:Amino Acid Transport Systems; D000818:Animals; D000831:Animals, Newborn; D001640:Bicuculline / Q000494:pharmacology; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D002642:Chick Embryo; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D018274:Electroporation / Q000379:methods; D004622:Embryo, Mammalian; D018756:GABA Antagonists / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental; D005968:Glutamate Decarboxylase / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D049452:Green Fluorescent Proteins; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000378:metabolism; D060850:LIM-Homeodomain Proteins; D008164:Luminescent Proteins / Q000378:metabolism; D008526:Medulla Oblongata / Q000166:cytology / Q000196:embryology / Q000254:growth & development; D008564:Membrane Potentials / Q000502:physiology; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors / Q000378:metabolism; D009433:Neural Inhibition / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D051762:PAX2 Transcription Factor; D018408:Patch-Clamp Techniques / Q000379:methods; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology / Q000196:embryology / Q000254:growth & development; D050777:Stathmin; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics; D050599:Vesicular Glutamate Transport Protein 2; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; D033921:Vesicular Transport Proteins; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D026905:Amino Acid Transport Systems; D001640:Bicuculline; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D018756:GABA Antagonists; D005968:Glutamate Decarboxylase; D018698:Glutamic Acid; D049452:Green Fluorescent Proteins; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D060850:LIM-Homeodomain Proteins; D008164:Luminescent Proteins; D026901:Membrane Transport Proteins; D009414:Nerve Growth Factors; D051762:PAX2 Transcription Factor; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D050777:Stathmin; D014157:Transcription Factors; D050599:Vesicular Glutamate Transport Protein 2; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; D033921:Vesicular Transport Proteins; D005680:gamma-Aminobutyric Acid; C112149:LIM homeobox transcription factor 1 beta; C497319:Pax2 protein, mouse; C493477:Slc17a6 protein, mouse; C512849:Stmn2 protein, mouse; C487378:Tlx1 protein, mouse; C487377:Tlx3 protein, mouse; C492244:Viaat protein, mouse; C402565:glutamate decarboxylase 1; C104722:glutamate receptor ionotropic, AMPA 2