Lbx1 and Tlx3 are opposing switches in determining GABAergic versus glutamatergic transmitter phenotypes.
Most neurons in vertebrates make a developmental choice between two principal neurotransmitter phenotypes (glutamatergic versus GABAergic). Here we show that the homeobox gene Lbx1 determines a GABAergic cell fate in the dorsal spinal cord at early embryonic stages. In Lbx1-/- mice, the presumptive GABAergic neurons are transformed into glutamatergic cells. Furthermore, overexpression of Lbx1 in the chick spinal cord is sufficient to induce GABAergic differentiation. Paradoxically, Lbx1 is also expressed in glutamatergic neurons. We previously reported that the homeobox genes Tlx1 and Tlx3 determine glutamatergic cell fate. Here we show that impaired glutamatergic differentiation, observed in Tlx3-/- mice, is restored in Tlx3-/-Lbx1-/- mice. These genetic studies suggest that Lbx1 expression defines a basal GABAergic differentiation state, and Tlx3 acts to antagonize Lbx1 to promote glutamatergic differentiation.
Cheng
Leping
L
Dana-Farber Cancer Institute, Harvard Medical School, 1 Jimmy Fund Way, Boston, Massachusetts 02115, USA.
Samad
Omar Abdel
OA
Xu
Yi
Y
Mizuguchi
Rumiko
R
Luo
Ping
P
Shirasawa
Senji
S
Goulding
Martyn
M
Ma
Qiufu
Q
D000818:Animals; D002452:Cell Count / Q000379:methods; D002454:Cell Differentiation / Q000502:physiology; D004622:Embryo, Mammalian; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009124:Muscle Proteins / Q000172:deficiency / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D010641:Phenotype; D013116:Spinal Cord / Q000166:cytology* / Q000196:embryology / Q000378:metabolism; D050599:Vesicular Glutamate Transport Protein 2 / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D018398:Homeodomain Proteins; D007527:Isoenzymes; C491868:Lbx1h protein, mouse; D009124:Muscle Proteins; C487377:Tlx3 protein, mouse; D050599:Vesicular Glutamate Transport Protein 2; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1