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A septo-temporal molecular gradient of sfrp3 in the dentate gyrus differentially regulates quiescent adult hippocampal neural stem cell activation.

Sun J, Bonaguidi MA, Jun H, Guo JU, Sun GJ, Will B, Yang Z, Jang MH, Song H, Ming GL, Christian KM - Mol Brain (2015)

Bottom Line: Using in situ hybridization and quantitative real-time PCR, we identified an inverse septal-to-temporal increase in the expression of sfrp3 that emerges during postnatal development.Elimination of sfrp3 and its molecular gradient leads to increased RGL activation, preferentially in the temporal region of the adult dentate gyrus.Our study identifies a niche mechanism that contributes to the graded distribution of neurogenesis in the adult dentate gyrus and has important implications for understanding functional differences associated with adult hippocampal neurogenesis along the septo-temporal axis.

View Article: PubMed Central - PubMed

Affiliation: Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing, 100084, P.R. China.

ABSTRACT

Background: A converging body of evidence indicates that levels of adult hippocampal neurogenesis vary along the septo-temporal axis of the dentate gyrus, but the molecular mechanisms underlying this regional heterogeneity are not known. We previously identified a niche mechanism regulating proliferation and neuronal development in the adult mouse dentate gyrus resulting from the activity-regulated expression of secreted frizzled-related protein 3 (sfrp3) by mature neurons, which suppresses activation of radial glia-like neural stem cells (RGLs) through inhibition of Wingless/INT (WNT) protein signaling.

Results: Here, we show that activation rates within the quiescent RGL population decrease gradually along the septo-temporal axis in the adult mouse dentate gyrus, as defined by MCM2 expression in RGLs. Using in situ hybridization and quantitative real-time PCR, we identified an inverse septal-to-temporal increase in the expression of sfrp3 that emerges during postnatal development. Elimination of sfrp3 and its molecular gradient leads to increased RGL activation, preferentially in the temporal region of the adult dentate gyrus.

Conclusions: Our study identifies a niche mechanism that contributes to the graded distribution of neurogenesis in the adult dentate gyrus and has important implications for understanding functional differences associated with adult hippocampal neurogenesis along the septo-temporal axis.

No MeSH data available.


Related in: MedlinePlus

Activation of quiescent radial glia-like neural stem cells (RGLs) along the septo-temporal axis of the adult hippocampus. a A schematic view of the mouse brain depicting the three-dimensional structure of the hippocampus and the orientation of the sections analyzed in this study. b Representative images of sections used for the analysis from septal (1a) to temporal (4c). The sections were stained with DAPI (grey). Scale bar, 100 μm. c Representative confocal images of immunostaining of MCM2 (red), nestin (green) and DAPI staining (blue) in the septal (left panel) and temporal (right panel) dentate gyrus of the same mouse. Inset, higher magnification views. Scale bars: 100 μm; inset, 25 μm. d Quantitative analysis of MCM2+nestin+ RGLs along the septo-temporal axis. Horizontal axis labels correspond to the numbers in Fig. 1a. Values represent mean ± S.E.M (n = 4)
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Fig1: Activation of quiescent radial glia-like neural stem cells (RGLs) along the septo-temporal axis of the adult hippocampus. a A schematic view of the mouse brain depicting the three-dimensional structure of the hippocampus and the orientation of the sections analyzed in this study. b Representative images of sections used for the analysis from septal (1a) to temporal (4c). The sections were stained with DAPI (grey). Scale bar, 100 μm. c Representative confocal images of immunostaining of MCM2 (red), nestin (green) and DAPI staining (blue) in the septal (left panel) and temporal (right panel) dentate gyrus of the same mouse. Inset, higher magnification views. Scale bars: 100 μm; inset, 25 μm. d Quantitative analysis of MCM2+nestin+ RGLs along the septo-temporal axis. Horizontal axis labels correspond to the numbers in Fig. 1a. Values represent mean ± S.E.M (n = 4)

Mentions: Due to the curvature and orientation of the hippocampus (Fig. 1a), sectioning the brain in one of the three traditional planes (coronal, horizontal, sagittal) produces sections in which the septo-temporal coordinates are hard to define. To better visualize adult hippocampal neurogenesis along the septo-temporal axis, we first established a new method for sectioning. We fixed hippocampi dissected from the adult mouse brain and embedded them into O.C.T. mounting solution. The individual hippocampus was positioned such that coronal-like sections were obtained from much of the septo-temporal extent of the structure (Fig. 1a-b). For quantification, we divided the hippocampus into four regions along the septo-temporal axis (Fig. 1a-b). Using this approach, we first investigated whether a difference in the activation of quiescent RGLs exists along the septo-temporal axis of the hippocampus of adult mice. We identified RGLs as nestin+ precursors localized within the sub-granular zone (SGZ) with radial processes extending towards the molecular layer [41] (Fig. 1c). We further used the expression of minichromosome maintenance complex component 2 (MCM2) as a marker for activation of largely quiescent RGLs since thymidine analogs such as EdU and BrdU are only incorporated during the S phase of cell cycle and preferentially label intermediate progenitors and neuroblasts with a single injection [41–46] (Fig. 1c). Stereological quantification along the SGZ in four regions showed a gradual decrease in the density of MCM2+ RGLs along the septo-temporal axis of the hippocampus (Fig. 1c-d). These results confirmed previous findings of septo-temporal differences in adult hippocampal neurogenesis [20] and further identified a clear gradient in which activation of quiescent adult neural stem cells decreases along the septo-temporal axis.Fig. 1


A septo-temporal molecular gradient of sfrp3 in the dentate gyrus differentially regulates quiescent adult hippocampal neural stem cell activation.

Sun J, Bonaguidi MA, Jun H, Guo JU, Sun GJ, Will B, Yang Z, Jang MH, Song H, Ming GL, Christian KM - Mol Brain (2015)

Activation of quiescent radial glia-like neural stem cells (RGLs) along the septo-temporal axis of the adult hippocampus. a A schematic view of the mouse brain depicting the three-dimensional structure of the hippocampus and the orientation of the sections analyzed in this study. b Representative images of sections used for the analysis from septal (1a) to temporal (4c). The sections were stained with DAPI (grey). Scale bar, 100 μm. c Representative confocal images of immunostaining of MCM2 (red), nestin (green) and DAPI staining (blue) in the septal (left panel) and temporal (right panel) dentate gyrus of the same mouse. Inset, higher magnification views. Scale bars: 100 μm; inset, 25 μm. d Quantitative analysis of MCM2+nestin+ RGLs along the septo-temporal axis. Horizontal axis labels correspond to the numbers in Fig. 1a. Values represent mean ± S.E.M (n = 4)
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Fig1: Activation of quiescent radial glia-like neural stem cells (RGLs) along the septo-temporal axis of the adult hippocampus. a A schematic view of the mouse brain depicting the three-dimensional structure of the hippocampus and the orientation of the sections analyzed in this study. b Representative images of sections used for the analysis from septal (1a) to temporal (4c). The sections were stained with DAPI (grey). Scale bar, 100 μm. c Representative confocal images of immunostaining of MCM2 (red), nestin (green) and DAPI staining (blue) in the septal (left panel) and temporal (right panel) dentate gyrus of the same mouse. Inset, higher magnification views. Scale bars: 100 μm; inset, 25 μm. d Quantitative analysis of MCM2+nestin+ RGLs along the septo-temporal axis. Horizontal axis labels correspond to the numbers in Fig. 1a. Values represent mean ± S.E.M (n = 4)
Mentions: Due to the curvature and orientation of the hippocampus (Fig. 1a), sectioning the brain in one of the three traditional planes (coronal, horizontal, sagittal) produces sections in which the septo-temporal coordinates are hard to define. To better visualize adult hippocampal neurogenesis along the septo-temporal axis, we first established a new method for sectioning. We fixed hippocampi dissected from the adult mouse brain and embedded them into O.C.T. mounting solution. The individual hippocampus was positioned such that coronal-like sections were obtained from much of the septo-temporal extent of the structure (Fig. 1a-b). For quantification, we divided the hippocampus into four regions along the septo-temporal axis (Fig. 1a-b). Using this approach, we first investigated whether a difference in the activation of quiescent RGLs exists along the septo-temporal axis of the hippocampus of adult mice. We identified RGLs as nestin+ precursors localized within the sub-granular zone (SGZ) with radial processes extending towards the molecular layer [41] (Fig. 1c). We further used the expression of minichromosome maintenance complex component 2 (MCM2) as a marker for activation of largely quiescent RGLs since thymidine analogs such as EdU and BrdU are only incorporated during the S phase of cell cycle and preferentially label intermediate progenitors and neuroblasts with a single injection [41–46] (Fig. 1c). Stereological quantification along the SGZ in four regions showed a gradual decrease in the density of MCM2+ RGLs along the septo-temporal axis of the hippocampus (Fig. 1c-d). These results confirmed previous findings of septo-temporal differences in adult hippocampal neurogenesis [20] and further identified a clear gradient in which activation of quiescent adult neural stem cells decreases along the septo-temporal axis.Fig. 1

Bottom Line: Using in situ hybridization and quantitative real-time PCR, we identified an inverse septal-to-temporal increase in the expression of sfrp3 that emerges during postnatal development.Elimination of sfrp3 and its molecular gradient leads to increased RGL activation, preferentially in the temporal region of the adult dentate gyrus.Our study identifies a niche mechanism that contributes to the graded distribution of neurogenesis in the adult dentate gyrus and has important implications for understanding functional differences associated with adult hippocampal neurogenesis along the septo-temporal axis.

View Article: PubMed Central - PubMed

Affiliation: Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing, 100084, P.R. China.

ABSTRACT

Background: A converging body of evidence indicates that levels of adult hippocampal neurogenesis vary along the septo-temporal axis of the dentate gyrus, but the molecular mechanisms underlying this regional heterogeneity are not known. We previously identified a niche mechanism regulating proliferation and neuronal development in the adult mouse dentate gyrus resulting from the activity-regulated expression of secreted frizzled-related protein 3 (sfrp3) by mature neurons, which suppresses activation of radial glia-like neural stem cells (RGLs) through inhibition of Wingless/INT (WNT) protein signaling.

Results: Here, we show that activation rates within the quiescent RGL population decrease gradually along the septo-temporal axis in the adult mouse dentate gyrus, as defined by MCM2 expression in RGLs. Using in situ hybridization and quantitative real-time PCR, we identified an inverse septal-to-temporal increase in the expression of sfrp3 that emerges during postnatal development. Elimination of sfrp3 and its molecular gradient leads to increased RGL activation, preferentially in the temporal region of the adult dentate gyrus.

Conclusions: Our study identifies a niche mechanism that contributes to the graded distribution of neurogenesis in the adult dentate gyrus and has important implications for understanding functional differences associated with adult hippocampal neurogenesis along the septo-temporal axis.

No MeSH data available.


Related in: MedlinePlus