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Results: 9

1.
Figure 3

Figure 3. From: Distinct Molecular Pathways for Development of Telencephalic Interneuron Subtypes Revealed Through Analysis of Lhx6 Mutants.

Laminar organization of cortical Lhx6+ interneurons and glutamatergic neurons in E18.5 Lhx6PLAP/+ and Lhx6PLAP/PLAP in coronal sections. The Lhx6+ interneurons were identified using rabbit anti-PLAP antibody (green) (A and A′) and the glutamatergic neurons (red) using the following antibodies: calretinin (CR) marks the neurons in the MZ (B and B′), CTIP2 identifies neurons in the layers VI and V (C and C′), and TBR1 labels the layer VI (D and D′). Abbreviations: see Table 3 and: II–IV: layers II, III and IV (cortical plate); V: layer V; VI: layer VI. Scale bar in A: 100 μm (for A–D and A′–D′).

Yangu Zhao, et al. J Comp Neurol. ;510(1):79-99.
2.
Figure 5

Figure 5. From: Distinct Molecular Pathways for Development of Telencephalic Interneuron Subtypes Revealed Through Analysis of Lhx6 Mutants.

Molecular features of the basal ganglia and cortex of Lhx6 PLAP/+ and Lhx6 PLAP/PLAP at E18.5 shown by in situ RNA hybridization on coronal hemisections, from a middle position along the rostrocaudal dimension. Two-fold higher magnification views of the cortex for each specimen are shown to the right. PLAP histochemistry is also shown. PLAP expression is nearly lost in the marginal zone (B, B′; arrowheads). Lhx6 (D, D′); Arx (H, H′); RDC1 (L, L′); ErbB4 (N, N′); and bMAF (R, R′) also show a decrease in marginal zone expression. Lhx6 (D, D′); Arx (H, H′); RDC1 (L, L′); ErbB4 (N, N′); SS (P, P′) and bMAF (R, R′) also show a decrease in cortical interneuron expression. Note: most of the neocortical NPY expression is in immature pyramidal cells at this age (S, S′, T, T′). Scale bar: 500 μm: low magnification’; 250 μm high magnification.

Yangu Zhao, et al. J Comp Neurol. ;510(1):79-99.
3.
Figure 9

Figure 9. From: Distinct Molecular Pathways for Development of Telencephalic Interneuron Subtypes Revealed Through Analysis of Lhx6 Mutants.

Model of molecular mechanisms that control development of striatal, cortical and hippocampal interneurons. MGE precursors express Nkx2.1 and Dlx; as they differentiate, they split into Nkx2.1+ and Nkx2.1. Nkx2.1+ differentiate into SS+ and NPY+ striatal interneurons. Nkx2.1;Lhx6+ cells become cortical and hippocampal interneurons, through the hypothesized actions of transcription factors (Arx, bMaf, Cux2 and NPAS1) and non-transcription factors (ErbB4, CXCR4, RDC1 and Thrombospondin). These cells generate the cortical and hippocampal PV+ and SS+ interneurons, and a subset of NPY+ (early-born) and CR+ interneurons. Precursors are located in the LGE and dorsal CGE (dCGE). These neurons express Dlx genes, but do not express Nkx2.1 or Lhx6, and may not use RDC1 and CXCR4 signaling. They differentiate into a different subset of CR+ and NPY+ (late born neurons) through the hypothesized actions of the Arx and NPAS1. We postulate that the early born NPY cortical/hippocampal interneurons are Lhx6-dependent, based on the loss of NPY expression in the E12.5 and E14.5 MGE; we provided evidence that late born NPY cortical/hippocampal interneurons are Lhx6-independent (Figs. 6, 7). See Supplemental Figure 22 for the magenta-green copy.

Yangu Zhao, et al. J Comp Neurol. ;510(1):79-99.
4.
Figure 8

Figure 8. From: Distinct Molecular Pathways for Development of Telencephalic Interneuron Subtypes Revealed Through Analysis of Lhx6 Mutants.

Striatal interneuron phenotypes in Lhx6 PLAP/PLAP (B, B′, D, D′, F, F′) mutant as compared to Lhx6 PLAP/+ control (A, A′, C, C′, E, E′). Parts of A–F are enlarged and shown in A′–F′. Immunohistochemical analysis on coronal hemisections from P17 animals showing a ~2-fold reduction of somatotstatin (SOM) (A, A′, B, B′) and neuropeptide Y (NPY) (C, C′, D, D′) cells, non-significant reduction in parvalbumin+ interneurons (PV) (E, E′, F, F′). Somatostatin: heterozygote: 268 +/− 23; homozygote: 112 +/− 5; P = 0.0003; NPY: heterozygote: 193 +/− 36; homozygote: 104 +/− 4; P = 0.013; parvalbumin: heterozygote: 243 +/− 41; homozygote: 204 +/− 58; P = 0.4; ChAT: heterozygote: 232 +/− 20; homozygote: 190 +/− 21; P = 0.07. Three animals for each genotype were examined. Arrowheads point to selected labeled cells. Note the change in neuropile staining and interneuron distribution. Scale bar in F′: 500 μm for A–F and 100 μm for A′–F′.

Yangu Zhao, et al. J Comp Neurol. ;510(1):79-99.
5.
Figure 6

Figure 6. From: Distinct Molecular Pathways for Development of Telencephalic Interneuron Subtypes Revealed Through Analysis of Lhx6 Mutants.

Cortical interneuron defects in Lhx6 PLAP/+ and Lhx6 PLAP/PLAP in coronal hemisections from P17 animals. Parvalbumin histochemical staining in the cortex of Lhx6 PLAP/PLAP animals is severely reduced (B′, B″), while NPY histochemical staining is increased (D′, D″). The cortex was split into two zones for counting analysis of in situ hybridization signals. Zone 1 includes roughly layers I–IV, and zone 2 includes roughly layers V–VI; the zones are demarcated by three horizontal lines (G′). The in situ hybridization analysis shows that the numbers of Dlx+ and GAD67+ cells in zone 1 don’t change significantly, whereas there was a ~2–3 fold increase in zone 2 in the Lhx6 PLAP/PLAP animals at P17 (G′–H″). Comparing Lhx6 PLAP/+ and Lhx6 PLAP/PLAP: Dlx1: Zone 1 (126 vs. 146); Zone 2: 112 vs. 223); GAD67: Zone 1 (272 vs. 318); Zone 2 (133 vs. 317); NPY: Zone 1 (68 vs. 353); Zone 2 (65 vs. 237). Scale bar: A–J: 1 mm; A′–J′:370 μm; A″–J″: 150 μm.

Yangu Zhao, et al. J Comp Neurol. ;510(1):79-99.
6.
Figure 4

Figure 4. From: Distinct Molecular Pathways for Development of Telencephalic Interneuron Subtypes Revealed Through Analysis of Lhx6 Mutants.

Molecular features of the basal ganglia and cortex of Lhx6 PLAP/+ and Lhx6 PLAP/PLAP at E12.5 and E14.5 shown by in situ RNA hybridization on coronal hemisections, from a middle position along the rostrocaudal dimension. PLAP histochemistry is also shown. Several markers show little or no change in expression in the MGE/LGE of Lhx6 PLAP/PLAP mutant animals; PLAP (A–B′), Dlx1 (E–F′), Arx (G–H′), GAD67 (I–J′) and Shh (W–X′). However, Lhx6 expression is reduced in the MGE at E14.5 (D, D′). ErbB4 expression is not detectable in the LGE (arrowheads; M, M′) and in cells migrating to the cortex (arrowheads; N, N′). The changes in expression of ErbB4 and SS in the LGE and ventral neocortex are shown at higher magnification (M″, M‴, N″, N‴). The same is true for RDC1 (K–L′), SS (O–P′) and NPY (S–T′). The MGE expression of ErbB4 appears relatively unaffected, while for RDC1 (K–L′), bMAF (Q–R′), NPY (S–T′) and Cux2 (U–V′) all show a dramatic reduction in expression (arrows). Abbreviations: Cx, Cortex; LGE, Lateral Ganglionic Eminence; MGE, Medial Ganglionic Eminence. Scale bar: A–X′, 500 μm.

Yangu Zhao, et al. J Comp Neurol. ;510(1):79-99.
7.
Figure 7

Figure 7. From: Distinct Molecular Pathways for Development of Telencephalic Interneuron Subtypes Revealed Through Analysis of Lhx6 Mutants.

Hippocampal interneuron phenotypes in Lhx6 PLAP/+ and Lhx6 PLAP/PLAP at E18.5, P11 and P17. While in situ hybridization and PLAP histochemistry shows a dramatic reduction in staining in the dorsomedial cortical plate and marginal zone in E18.5 Lhx6 PLAP/PLAP animals (arrowheads; A–D′), the hippocampus maintains its PLAP staining (arrow; A, A′). Similar results are seen for Arx (B, B′), Dlx1 (C, C′), GAD67 (D, D′) and NPAS1 (K, K′) at E18.5. Note how hippocampal expression of NPY (E, E′) is maintained in the same region showing PLAP, Arx, Dlx1, GAD67 and NPAS1 expression. At P11, there is ~2-fold increase in the number of NPAS1 immunoreactive cells in hippocampal interneuron layers (easiest to see in stratum radiatum, SR) in the Lhx6 PLAP/PLAP animals (F′). NPY+ cells in the hippocampus completely co-label with Dlx2 (G), but there are more Dlx2+/NPY cells in the Lhx6 PLAP/PLAP animals at P11 (G′). Note the reduction of NPY+ processes. Cell counting in rostral hippocampal P17 sections (H–J′): Dlx1+: 143±36 (Lhx6 PLAP/+); 156±34 (Lhx6 PLAP/PLAP) (p=0.7); GAD67+: 289±45 vs. 281±39 (p=0.7); NPY+: 141±20 vs. 196±50 (p=0.1). Abbreviations: Hc, Hippocampus; MZ, Marginal Zone; SR, Stratum Radiatum; SP, Stratum Pyramidale. Scale bar: A–E′: 700 μm; F–F′:480 μm; G–G′: 80 μm; H–J′: 500 μm. See Supplemental Figure 21 for the magenta-green copy.

Yangu Zhao, et al. J Comp Neurol. ;510(1):79-99.
8.
Figure 2

Figure 2. From: Distinct Molecular Pathways for Development of Telencephalic Interneuron Subtypes Revealed Through Analysis of Lhx6 Mutants.

Analysis of the position of Lhx6-expressing cells in the cortex and basal ganglia of Lhx6PLAP/+ and Lhx6PLAP/PLAP of coronal hemisections from E14.5 and E18.5 using alkaline phosphatase histochemical reaction to visualize the Lhx6+ cells. E14.5 data are shown in panels A–A″ and B–B″ and E18.5 data are shown in panels C–C″ and D–D″. Telencephalic left hemisphere (left column); higher magnification view of the ganglionic eminences and cortex (middle column); High magnification view of the cortex (right column; boxes in the middle column identify these regions). At E14.5, there is a retardation of the dorsal progression of the tangentially migrating PLAP+ cortical cells in the mutant (Figure 2A′, 2B′). At E18.5, the distribution of the PLAP+ cells is strongly affected in the mutant compared to the control. In the mutant, there is a large reduction in PLAP+ cells of the MZ and upper CP (figure 2C′ and 2D′), whereas there is an excess of PLAP+ cells in the lower part of the CP, the IZ and the SVZ (figure 2C′ and 2D′). There is a ventrodorsal gradient in the phenotype; the dorsomedial cortex is most affected. Abbreviations: see Table 3 and CX: cortex; GP: globus pallidus; LGE: lateral ganglionic eminence; MGE: medial ganglionic eminence; St: striatum. Scale bar for A and B: 500 μm; for C and D: 500 μm; for A′–D′: 200 μm; for A″–D″: 50 μm.

Yangu Zhao, et al. J Comp Neurol. ;510(1):79-99.
9.
Figure 1

Figure 1. From: Distinct Molecular Pathways for Development of Telencephalic Interneuron Subtypes Revealed Through Analysis of Lhx6 Mutants.

Analysis of Dlx2 and Lhx6 co-expression in the cortex of Lhx6PLAP/+ and Lhx6PLAP/PLAP at E14.5 and E18.5 by immunofluorescence of coronal sections. E14.5 data are shown in panels A–A’’’’ and B–B’’’’ and E18.5 data are shown in panels C–C’’’’ and D–D’’’’. PLAP expression was used to identify Lhx6+ cells. DLX2 immunofluorescence (red; first column); PLAP immunofluorescence (IF) (green; second column); merged (third column); higher magnification of marginal zone and cortical plate (see boxes in A″, B″, C″ and D″)(fourth column). Low magnification views of PLAP expression (histochemically-stained, HC) in telencephalic hemispheres (fifth column); boxed regions correspond to the approximate regions shown in the panels to the left. The boxes in the panels in the third column identify the regions shown at higher magnification in the fourth column. Panels C, C′ and C″ and D, D′ and D″ are composite images from the fusion of 2 images (confocal pictures; 25x objective) from the superficial region of the cortex and the deep region of the cortex.
At E14.5, the mutant has slightly reduced numbers of PLAP+ cortical interneurons compared to the heterozygote (A′ and B′), while at E18.5, the distribution of the PLAP+ cells in the mutant is very abnormal; compare with the heterozygote (C′ and D′). The mutant had very few PLAP+ cells in the superficial layers of the cortex (MZ and superficial layers of the CP). By contrast, the mutant had increased numbers of PLAP+ cells in deep regions of the CP and IZ (C′ and D′). At E14.5, Lhx6PLAP/+ and Lhx6PLAP/PLAP only exhibited interneurons that were Dlx2+;Lhx6+ (A″, A‴ and B″, B‴); whereas by E18.5, there were Dlx2 +;Lhx6 and Dlx2+;Lhx6+. Abbreviations: see Table: 3. Scale bar in A: 50 μm (for A–D, A′–D′ and A″–D″). Scale bar for A‴–B‴: 10 μm; for C‴ and D‴: 20 μm; for A’’’’ and B’’’’: 1mm; for C’’’’ and D’’’’: 1mm. See Supplemental Figure 20 for the magenta-green copy.

Yangu Zhao, et al. J Comp Neurol. ;510(1):79-99.

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