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. 2005 Jan 5;25(1):247-51.
doi: 10.1523/JNEUROSCI.2899-04.2005.

Pax6, Tbr2, and Tbr1 are expressed sequentially by radial glia, intermediate progenitor cells, and postmitotic neurons in developing neocortex

Chris Englund  1 , Andy Fink, Charmaine Lau, Diane Pham, Ray A M Daza, Alessandro Bulfone, Tom Kowalczyk, Robert F Hevner
Affiliations

Pax6, Tbr2, and Tbr1 are expressed sequentially by radial glia, intermediate progenitor cells, and postmitotic neurons in developing neocortex

Chris Englund et al. J Neurosci. .

Abstract

The developing neocortex contains two types of progenitor cells for glutamatergic, pyramidal-projection neurons. The first type, radial glia, produce neurons and glia, divide at the ventricular surface, and express Pax6, a homeodomain transcription factor. The second type, intermediate progenitor cells, are derived from radial glia, produce only neurons, and divide away from the ventricular surface. Here we show that the transition from radial glia to intermediate progenitor cell is associated with upregulation of Tbr2, a T-domain transcription factor, and downregulation of Pax6. Accordingly, Tbr2 expression in progenitor compartments (the subventricular zone and ventricular zone) rises and falls with cortical plate neurogenesis. The subsequent transition from intermediate progenitor cell to postmitotic neuron is marked by downregulation of Tbr2 and upregulation of Tbr1, another T-domain transcription factor. These findings delineate the transcription factor sequence Pax6 --> Tbr2 --> Tbr1 in the differentiation of radial glia --> intermediate progenitor cell --> postmitotic projection neuron. This transcription factor sequence is modified in preplate neurons, in which Tbr2 is transiently coexpressed with Tbr1, and in the direct differentiation pathway from radial glia --> postmitotic projection neuron, in which Tbr2 is expressed briefly or not at all.

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Figures

Figure 1.
Figure 1.
Expression of Pax6, Tbr2, and Tbr1 protein in E14.5 cortex (coronal sections). A, C, Pax6 (green) and Tbr2 (red). Boxed area in A is shown at higher magnification in C. B, D, Pax6 (green) and Tbr1 (red). Boxed area in B is shown at higher magnification in D. E, Tbr2 (green) and Tbr1 (red). All three TFs were expressed in the neocortex (nctx) and eminentia thalami (emt). Pax6 was also expressed in the ventricular zone of the dorsal thalamus (dt), hypothalamus (hy), and lateral part of the lateral ganglionic eminence (lge). Within the neocortex, Pax6 was expressed in the ventricular zone (vz) only; Tbr2 was expressed in the ventricular zone, subventricular zone (svz), and intermediate zone (iz); and Tbr1 was expressed in the intermediate zone (iz), subplate (sp), cortical plate (cp), and marginal zone (mz). Rarely, Tbr2+ cells and Pax6+ cells occupied superficial zones (arrowheads in C). Scale bar (in A): A, B, 500 μm; C-E,50 μm.
Figure 2.
Figure 2.
Tbr2 is expressed by NS-div IPCs. A-S, Confocal images of coronal sections through E14.5 cortex. A-D, Tbr2 (red) and BrdU (green). The bracketed area in A is shown in separate color channels in B-D. Tbr2 was expressed by most S-phase cells in the SVZ and some in the VZ (arrowheads in B-D). E-G, Tbr2 (red) and DNA (blue). Tbr2 was expressed by NS-div cells (red arrowhead in E-G) but not by S-div cells (green arrowheads). H-J, Tbr2 (red) was expressed by phosphovimentin+ (p-vim) M-phase cells (green) in the SVZ (arrowheads). K-M, Tbr2 (red) and PCNA (green). Most Tbr2+ cells contained PCNA, including mitotic figures (arrowheads). N, Tbr2 (red) and nestin (green). Most Tbr2+ cells (arrowheads) appeared to lack nestin. O, Tbr2 (red) and βIII-tubulin (β-tub; green). Most Tbr2+ cells (arrowheads) lacked βIII-tubulin. P-S, Tbr2 (red), NeuN (green), and DNA (blue). The bracketed area in P is enlarged and shown in separate color channels in Q-S. Most Tbr2+ cells did not express NeuN, but those that did included some mitotic figures (arrowheads in Q-S). T-V, E14.5 cortical cells cultured for 1 d in vitro, labeled to detect Tbr2 (red), DNA (blue), and, in green, nestin (T), βIII-tubulin (U), or NeuN (V). Few Tbr2+ cells expressed nestin (5.1%) or βIII-tubulin (12.7%), but more expressed NeuN (20.8%; arrowheads). Scale bars: (in A) A-D, P, 50 μm; (in E) E-G, 20 μm; (in H) H-J, Q-S, 10 μm; (in K) K-M, O, 10 μm; (in N) N, 20 μm; (in T) T-V, 20 μm.
Figure 3.
Figure 3.
Pax6 is substantially downregulated in most Tbr2+ IPCs. A-I, Confocal images of coronal sections through E14.5 cortex. A-D, Pax6 (green) and BrdU (red). The bracketed area in A is shown in separate color channels in B-D. Pax6 was not expressed by most S-phase cells in the SVZ (arrowheads in B-D) but was expressed by most S-phase cells in the VZ. E, Pax6 (green) and phosphohistone-H3 (red). Pax6 was strongly expressed in S-div mitotic figures (arrowheads) but only weakly (yellow arrow) or not at all (white arrow) in NS-div cells. F-I, Pax6 (green) and Tbr2 (red) double immunofluorescence. Most VZ and SVZ cells expressed Pax6 or Tbr2 but not both. Double-labeled cells appeared yellow (arrowheads in G). H-I, Higher magnification of mitotic figures in the SVZ (H) and VZ (I). NS-div mitoses were predominantly Tbr2+ (arrowhead in H), and S-div mitoses were Pax6+ (arrowheads in I). Scale bar (in A): A-E,30 μm; F,40 μm; G-I,12 μm.
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