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. 2012 Jun 20;32(25):8509-20.
doi: 10.1523/JNEUROSCI.6301-11.2012.

Tlx1/3 and Ptf1a control the expression of distinct sets of transmitter and peptide receptor genes in the developing dorsal spinal cord

Zhen Guo  1 , Congling Zhao, Menggui Huang, Tianwen Huang, Mingran Fan, Zhiqin Xie, Ying Chen, Xiaolin Zhao, Guannan Xia, Junlan Geng, Leping Cheng
Affiliations

Tlx1/3 and Ptf1a control the expression of distinct sets of transmitter and peptide receptor genes in the developing dorsal spinal cord

Zhen Guo et al. J Neurosci. .

Abstract

Establishing the pattern of expression of transmitters and peptides as well as their receptors in different neuronal types is crucial for understanding the circuitry in various regions of the brain. Previous studies have demonstrated that the transmitter and peptide phenotypes in mouse dorsal spinal cord neurons are determined by the transcription factors Tlx1/3 and Ptf1a. Here we show that these transcription factors also determine the expression of two distinct sets of transmitter and peptide receptor genes in this region. We have screened the expression of 78 receptor genes in the spinal dorsal horn by in situ hybridization. We found that receptor genes Gabra1, Gabra5, Gabrb2, Gria3, Grin3a, Grin3b, Galr1, and Npy1r were preferentially expressed in Tlx3-expressing glutamatergic neurons and their derivatives, and deletion of Tlx1 and Tlx3 resulted in the loss of expression of these receptor genes. Furthermore, we obtained genetic evidence that Tlx3 uses distinct pathways to control the expression of receptor genes. We also found that receptor genes Grm3, Grm4, Grm5, Grik1, Grik2, Grik3, and Sstr2 were mainly expressed in Pax2-expressing GABAergic neurons in the spinal dorsal horn, and their expression in this region was abolished or markedly reduced in Ptf1a and Pax2 deletion mutant mice. Together, our studies indicate that Tlx1/3 and Ptf1a, the key transcription factors for fate determination of glutamatergic and GABAergic neurons in the dorsal spinal cord, are also responsible for controlling the expression of two distinct sets of transmitter and peptide receptor genes.

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Figures

Figure 1.
Figure 1.
Expression of receptor/subunit genes in the developing spinal cord of mouse. A1–F4, In situ hybridization was performed on sections of mouse spinal cord at different developmental stages (E14.5 to P7) using various receptor/subunit genes as probes. A1–B4, Gabra1 and Gabrb2 were weakly expressed in the dorsal horn at E16.5. At P0 and P7, the expression of Gabra1 and Gabrb2 was enriched in laminae II/III of the dorsal horn (A3, A4, B3, B4, arrows). C1–C4, At E14.5, Grm3 was expressed in the dorsal horn (C1, arrow). From E16.5 to P7, Grm3 was enriched in laminae II/III neurons of the dorsal horn (C2–C4, arrows). D1–D4, From E14.5 to P7, Grin3a expression was enriched in the superficial laminae (D1–D4, arrows). E1–E4, From E16.5 to P7, Sstr2 was expressed in superficial laminae neurons (E2–E4, arrows). F1–F4, From E14.5 to P7, Npy1r was expressed in superficial laminae neurons of the dorsal horn (arrows). Scale bars, 100 μm.
Figure 2.
Figure 2.
Expression of receptor/subunit genes Gabra1, Gabrb2, Gria3, Grin3a, and Npy1r in Tlx3+ or Pax2+ neurons. A1–J2, Double staining of Tlx3 protein (A2, C2, E2, G2, I2, green) or Pax2 protein (B2, D2, F2, H2, J2, green) with Gabra1 (A2, B2, red), Gabrb2 (C2, D2, red), Gria3 (E2, F2, red), Grin3a (G2, H2, red), or Npy1r (I2, J2, red) mRNA on spinal cord sections at indicated stages. Bright-field in situ hybridization signals were converted into red pseudocolor signals. Note the colocalization of Gabra1, Gabrb2, Gria3, Grin3a, and Npy1r with Tlx3 (A2, C2, E2, G2, I2, arrows) but not with Pax2 (B2, D2, F2, H2, J2). Scale bars: A1, B1, C1, D1, E1, F1, G1, H1, I1, J1, 50 μm; A2, B2, C2, D2, E2, F2, G2, H2, I2, J2, 20 μm.
Figure 3.
Figure 3.
Expression of Gabra1, Gabrb2, Gria3, Grin3a, and Npy1r in Tlx3+ derivatives. A–J, Double staining of LacZ protein with Gabra1, Gabrb2, Gria3, Grin3a, or Npy1r on spinal sections of Tau–nLacZ (Tlx3cre) mice at P0. LacZ+ neurons represent Tlx3+ derivatives. Bright-field in situ hybridization signals were converted into red pseudocolor signals. Note the colocalization of Gabra1, Gabrb2, Gria3, Grin3a, and Npy1r with LacZ (B, D, F, H, J, arrows) in the dorsal horn. Scale bars: A, C, E, G, I, 50 μm; B, D, F, H, J, 20 μm.
Figure 4.
Figure 4.
Expression of Grm3, Grm5, Grik1, and Sstr2 in Pax2+ or Tlx3+ neurons. A–P, Double staining of Pax2 protein (B, F, J, N, green) or Tlx3 protein (D, H, L, P, green) with Grm3 (B, D, red), Grm5 (F, H, red), Grik1 (J, L, red), or Sstr2 (N, P, red) mRNA on spinal cord sections at indicated stages. Bright-field in situ hybridization signals were converted into red pseudocolor signals. Note the colocalization of Grm3, Grm5, Grik1, and Sstr2 with Pax2 (B, F, J, N, arrows) but not Tlx3 (D, H, L, P). Scale bars: A, C, E, G, I, K, M, O, 50 μm; B, D, F, H, J, L, N, P, 20 μm.
Figure 5.
Figure 5.
Expression of receptor/subunit genes in Tlx1/3−/− mice. A–L, In situ hybridization was performed on sections of wild-type or Tlx1/3−/− spinal cord at E14.5, E16.5, or E18.5. A–J, Note the loss of expression of Gabra1, Gabrb2, Grin3a, Galr1, and Npy1r in the dorsal horn of Tlx1/3−/− mice (arrows). K, L, Note the increase of Grm3 expression in the dorsal horn of Tlx1/3−/− mice (arrow). Scale bars, 100 μm.
Figure 6.
Figure 6.
Expression of receptor/subunit genes in Tlx3−/−, Lbx1−/−, and Tlx3−/−;Lbx1−/− mice. A–P, In situ hybridization was performed on sections of spinal cord from E14.5 embryos (with indicated genotypes). A–L, Note the loss of expression of Gria2, Galr1, and Npy1r in the superficial laminae of the dorsal horn in Tlx3−/−, Lbx1−/−, and Tlx3−/−;Lbx1−/− mice (arrows). M–P, Gria3 expression was markedly reduced in the dorsal horn of Tlx3−/− mice, de-repressed in the dorsal horn of Lbx1−/− mice, and restored in the dorsal horn of Tlx3−/−;Lbx1−/− mice. Scale bars, 100 μm.
Figure 7.
Figure 7.
Expression of receptor/subunit genes Grik1, Grik2, Grm3, Grm5, Sstr2, and Npy1r in Ptf1a−/− mice. A–L, In situ hybridization was performed on spinal cord sections of wild-type or Ptf1a−/− mice at E14.5, E16.5, or E18.5. A–J, Note the loss or reduction of expression of Grik1, Grik2, Grm3, Grm5, and Sstr2 in the dorsal horn of Ptf1a−/− mice (arrows). K, L, Note the increase of Npy1r expression in the dorsal horn of Ptf1a−/− mice (arrow). Scale bars, 100 μm.
Figure 8.
Figure 8.
Expression of receptor/subunit genes Grik2, Grik3, Grm3, Grm5, and Sstr2 in Pax2−/− mice. A–J, In situ hybridization was performed on sections of spinal cord from wild-type or Pax2−/− mice at E18.5. Note the loss or marked reduction of expression of Grik2, Grik3, Grm3, Grm5, and Sstr2 in the dorsal horn of Pax2−/− mice. Scale bars, 100 μm.
Figure 9.
Figure 9.
A model for the roles of transcription factors Tlx1/3, Lbx1, Ptf1a, and Pax2 in controlling the expression of transmitter and peptide receptor/subunit genes in the dorsal spinal cord. A, Tlx1/3 are required for the expression of Gabra1, Grin3a, Grin3b, and Tacr1. Both Tlx3 and Lbx1 are required for the expression of Gria2, Galr1, and Npy1r. Tlx3 acts to antagonize Lbx1 to control the expression of Gria3. Tlx1/3 are required for the expression of Gabra5 and Gabrb2 as well, whereas Ptf1a suppresses the expression of Npy1r, Gabra5, and Gabrb2. B, Ptf1a and Pax2 are required for the expression of Grik1, Grik2, Grik3, Grm3, Grm4, Grm5, and Sstr2, whereas Tlx1/3 suppress the expression of Grik1, Grik2, Grik3, Grm3, Grm4, and Grm5.
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