Lbx1 and Tlx3 are opposing switches in determining GABAergic versus glutamatergic transmitter phenotypes

• DOI: 10.1038/nn1569
• Publication Date: 2005-10-18T18:36:46Z
• Authors: Leping Cheng; Omar Abdel Samad; Yi Xu; Rumiko Mizuguchi; Ping Luo; Senji Shirasawa; Martyn Goulding; Qiufu Ma
• Keywords: Homeodomain Proteins; Neurons; 0301 basic medicine; Glutamate Decarboxylase; Glutamic Acid; Muscle Proteins; Cell Count; Cell Differentiation; Embryo, Mammalian; Immunohistochemistry; Mice, Mutant Strains; Isoenzymes; Mice; 03 medical and health sciences; Phenotype; Spinal Cord; Vesicular Glutamate Transport Protein 2; Animals; In Situ Hybridization; gamma-Aminobutyric Acid

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.