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. 2010 Oct 20:11:136.
doi: 10.1186/1471-2202-11-136.

The p75 neurotrophin receptor is expressed by adult mouse dentate progenitor cells and regulates neuronal and non-neuronal cell genesis

Ramon O Bernabeu  1 , Frank M Longo
Affiliations

The p75 neurotrophin receptor is expressed by adult mouse dentate progenitor cells and regulates neuronal and non-neuronal cell genesis

Ramon O Bernabeu et al. BMC Neurosci. .

Abstract

Background: The ability to regulate neurogenesis in the adult dentate gyrus will require further identification and characterization of the receptors regulating this process. In vitro and in vivo studies have demonstrated that neurotrophins and the p75 neurotrophin receptor (p75NTR) can promote neurogenesis; therefore we tested the hypothesis that p75NTR is expressed by adult dentate gyrus progenitor cells and is required for their proliferation and differentiation.

Results: In a first series of studies focusing on proliferation, mice received a single BrdU injection and were sacrificed 2, 10 and 48 hours later. Proliferating, BrdU-positive cells were found to express p75NTR. In a second series of studies, BrdU was administered by six daily injections and mice were sacrificed 1 day later. Dentate gyrus sections demonstrated a large proportion of BrdU/p75NTR co-expressing cells expressing either the NeuN neuronal or GFAP glial marker, indicating that p75NTR expression persists at least until early stages of maturation. In p75NTR (-/-) mice, there was a 59% decrease in the number of BrdU-positive cells, with decreases in the number of BrdU cells co-labeled with NeuN, GFAP or neither marker of 35%, 60% and 64%, respectively.

Conclusions: These findings demonstrate that p75NTR is expressed by adult dentate progenitor cells and point to p75NTR as an important receptor promoting the proliferation and/or early maturation of not only neural, but also glial and other cell types.

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Figures

Figure 1
Figure 1
p75NTR expression in BrdU-positive SGZ cells, 10 hours post-BrdU injection. Dentate gyrus coronal sections harvested from p75NTR (+/+) mice 10 hours after a single BrdU injection were co-immunostained with antibodies against BrdU (red) and p75NTR (green). Confocal microscope Z-stacks were collected at 40 × magnification with an interval of 1 μm between planes with a total of 6 image planes collected from each section. The typical appearance of SGZ fields is shown here. Scale bar (lower right panel): 2 μm.
Figure 2
Figure 2
p75NTR expression in BrdU-positive SGZ cells, 2 hours and 2 days post-BrdU injection. Dentate gyrus coronal sections harvested from p75NTR (+/+) mice 2 hours or 2 days after a single BrdU injection were co-immunostained with antibodies against BrdU (red) and p75NTR (green). Stereological estimates (as described in Methods) were used to quantitate the total number of BrdU-positive cells per dentate gyrus (open triangles) and BrdU-positive cells expressing p75NTR (closed circles) (*** p < 0.001, Student-Newman-Keuls test after ANOVA, n = 6 mice with right and left dentate gyri averaged for each mouse). Scale bar: 200 μm.
Figure 3
Figure 3
Confocal image analysis of BrdU, NeuN and p75 NTR co-immunostaining. Coronal sections of the dentate gyrus derived from a p75 NTR (+/-) mouse were examined. Tissue was obtained one day following the 6 day BrdU injection protocol. (A) BrdU antibody (red) detects cells primarily located in the SGZ and hilus. (B) NeuN staining (green) demonstrates the characteristic pattern of granule cell layer neurons in the dentate gyrus along with individual cells apparent in the subgranular zone and hilus. (C) p75 NTR staining (blue) identifies cells in the SGZ and hilus. (D) Overlay of images shown in A-C reveals cells co-labeled with BrdU, NeuN and p75 NTR (white, horizontal arrow); BrdU and p75 NTR (pink, up-down arrow); BrdU alone (red); BrdU and NeuN (yellow, down-up arrow). Scale bar: 300 μm. Inset in figure C: high magnification of p75NTR staining in p75NTR (+/+) (1) and (-/-) (2) mice.
Figure 4
Figure 4
Confocal image analysis of BrdU, GFAP and p75NTR co-immunostaining. Coronal sections of the dentate gyrus derived from a p75 NTR (+/-) mouse ware examined. Tissue was obtained one day following the 6 day BrdU injection protocol. (A) BrdU antibody (red) detects cells primarily located in the SGZ and hilus. (B) GFAP staining (purple) demonstrates a characteristic fibrillar pattern of astrocytes in the dentate gyrus. (C) p75 NTR staining (green) identifies cells in the SGZ. (D) Overlay of images shown in A-C reveals cells co-labeled with BrdU, GFAP and p75 NTR (white, horizontal arrow); BrdU and p75 NTR (yellow, down-up arrow); BrdU and GFAP (pink, up-down arrow); GFAP and p75 NTR (cyan) and BrdU alone (red). Scale bar: 100 μm.
Figure 5
Figure 5
Light microscopy analysis of BrdU-positive cells in p75NTR (+/+) and (-/-) dentate gyrus. Coronal sections of the dentate gyrus harvested from p75 NTR (+/+) (B, D) and p75 NTR (-/-) (C, E) transgenic mice were examined. (A) Coronal schematic of anterior and posterior dentate gyrus (modified from [54]). In p75 NTR (+/+) tissues (B and D), BrdU-positive cells are found in a characteristic arrangement in the SGZ adjacent to the dentate gyrus in both anterior (B) and posterior (D) sections. Labeled cells are also present in the hilar regions (arrows). In p75 NTR (-/-) mice (C and E) an apparent decrease in the number of BrdU-positive cells was found in both anterior (C) and posterior (E) regions. Labeled cells are absent in the hilar regions in p75NTR (-/-) (arrows in C and E). (F, G) Higher magnification of labeled SGZ cells demonstrates characteristic aggregation of progenitor cells in p75NTR (+/+) sections with less aggregate apparent in (-/-) sections. Scale bar 25 μm. Abbreviations: ant: anterior; post: posterior; sgz: subgranular zone; DG: dentate gyrus. Scale bar: 100 μm.
Figure 6
Figure 6
Quantification of BrdU-positive cells in p75NTR (+/+) and (-/-) mice. Dentate gyrus volume and numbers of BrdU-positive cells were measured in coronal sections harvested from p75 NTR (+/+) and (-/-) mice. Tissues were obtained one day following the 6-day BrdU injection protocol. (A) Cell counts (as determined by stereological estimates (as described in Methods) in p75 NTR (-/-) mice (n = 14 mice) were significantly decreased compared to those in p75 NTR (+/+) mice (n = 9). *** p < 0.001 between groups, using Student-Newman-Keuls test after ANOVA. For each mouse the cell counts in right and left dentate gyri were averaged. (B) No difference in volume of the granular cell layer was detected between p75 NTR (+/+) and (-/-) mice (mean ± SE; n = 6 mice per group).
Figure 7
Figure 7
Confocal image analysis of BrdU, NeuN and GFAP co-immunostaining in p75NTR (+/+) and (-/-) mice. Coronal sections of the dentate gyrus were co-immunostained with antibodies directed against BrdU (red), NeuN (green) and GFAP (blue). Sections harvested from p75 NTR (+/+) (A, anterior; C, posterior) and p75 NTR (-/-) (B, anterior; D, posterior) mice one day following the 6-day BrdU protocol were examined. Sections from p75 NTR (-/-) mice (B-D) demonstrate an apparent decrease in the number of SGZ BrdU-positive neurons colocalizing with NeuN marker (yellow) compared to wildtype mice (A-C). (E): Insert: cells staining for BrdU and NeuN (yellow); BrdU and GFAP (pink); BrdU (red); NeuN (green) and GFAP (blue). Scale bar, A-D: 300 μm and E: 15 μm.
Figure 8
Figure 8
Quantitative analysis of NeuN and GFAP markers expressed by BrdU-positive cells. Coronal sections of the dentate gyrus were co-immunostained with antibodies directed against BrdU, NeuN and GFAP as demonstrated in Figure 7. The numbers of BrdU-positive cells co-labeling with NeuN, GFAP or neither marker were determined by stereological estimates (as described in Methods). For each mouse the cell counts in right and left dentate gyri were averaged. (A) A significant decrease in the number of BrdU-positive cells co-expressing NeuN, GFAP and neither marker was found in p75 NTR (-/-) sections. (B) The percentage of BrdU-positive cells expressing NeuN, GFAP and neither marker are indicated. BrdU-positive cells co-labeling with NeuN demonstrated a significant increase from 66% in p75NTR (+/+) mice to 81% in (-/-) mice. *** p < 0.001, ** p < 0.01, between groups, using Student-Newman-Keuls test after ANOVA (n = 6 (+/+) and 8 (-/-) mice).
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