Abstract
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.
MeSH Terms
Amino Acid Transport Systems
Animals
Animals, Newborn
Bicuculline/pharmacology
Calcium-Binding Proteins
Carrier Proteins/genetics,metabolism
Cell Count/methods
Cell Differentiation/genetics,physiology
Cells, Cultured
Chick Embryo
DNA-Binding Proteins/deficiency,genetics
Electroporation/methods
Embryo, Mammalian
GABA Antagonists/pharmacology
Gene Expression Regulation, Developmental
Glutamate Decarboxylase/metabolism
Glutamic Acid/metabolism
Green Fluorescent Proteins
Homeodomain Proteins/genetics,metabolism,physiology
Immunohistochemistry/methods
In Situ Hybridization/methods
Intracellular Signaling Peptides and Proteins
Isoenzymes/metabolism
LIM-Homeodomain Proteins
Luminescent Proteins/metabolism
Medulla Oblongata/cytology,embryology,growth & development
Membrane Potentials/physiology
Membrane Transport Proteins
Mice
Mice, Knockout
Molecular Sequence Data
Nerve Growth Factors/metabolism
Neural Inhibition/drug effects
Neurons/drug effects,physiology
PAX2 Transcription Factor
Patch-Clamp Techniques/methods
Receptors, AMPA/genetics,metabolism
Receptors, Kainic Acid/genetics,metabolism
Spinal Cord/cytology,embryology,growth & development
Stathmin
Transcription Factors/deficiency,genetics
Vesicular Glutamate Transport Protein 2
Vesicular Inhibitory Amino Acid Transport Proteins
Vesicular Transport Proteins
gamma-Aminobutyric Acid/metabolism
Chemicals
Amino Acid Transport Systems
Calcium-Binding Proteins
Carrier Proteins
DNA-Binding Proteins
GABA Antagonists
Homeodomain Proteins
Intracellular Signaling Peptides and Proteins
Isoenzymes
LIM homeobox transcription factor 1 beta
LIM-Homeodomain Proteins
Luminescent Proteins
Membrane Transport Proteins
Nerve Growth Factors
PAX2 Transcription Factor
Pax2 protein, mouse
Receptors, AMPA
Receptors, Kainic Acid
Slc17a6 protein, mouse
Stathmin
Stmn2 protein, mouse
Tlx1 protein, mouse
Tlx3 protein, mouse
Transcription Factors
Vesicular Glutamate Transport Protein 2
Vesicular Inhibitory Amino Acid Transport Proteins
Vesicular Transport Proteins
Viaat protein, mouse
Green Fluorescent Proteins
Glutamic Acid
gamma-Aminobutyric Acid
Glutamate Decarboxylase
glutamate decarboxylase 1
glutamate receptor ionotropic, AMPA 2
Bicuculline
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Cheng Leping
The Dana-Farber Cancer Institute, and Department of Neurobiology, Harvard Medical School, 1 Jimmy Fund Way, Boston, Massachusetts 02115, USA.
Arata Akiko
Mizuguchi Rumiko
Qian Ying
Karunaratne Asanka
Gray Paul A
Arata Satoru
Shirasawa Senji
Bouchard Maxime
Luo Ping
Chen Chih-Li
Busslinger Meinrad
Goulding Martyn
Onimaru Hiroshi
Ma Qiufu
