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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 increases in adult sfrp3 knockout (KO) mice. a Quantitative analysis of MCM2+nestin+ RGLs along the septo-temporal axis of adult sfrp3 KO and wildtype (WT) littermates. Values present mean ± S.E.M. [n = 6 (KO), 7 (WT)]. b Higher relative increase in RGL activation in the temporal dentate gyrus of adult sfrp3 KO mice. Same groups of animals in Fig. 4b were analyzed. Data were normalized to control WT group from septal (1) to temporal (4) dentate gyrus. c Representative confocal images of immunostaining of GFP (green) for quiescent and activated clones in the adult nestin-CreERT2+/−;Z/EGf/+; sfrp3−/− KO mice and nestin-CreERT2+/−;Z/EGf/+; sfrp3+/+ control mice. Scale bar = 10 μm. d Quantification of increased RGL activation at both septal and temporal poles in the dentate gyrus of adult sfrp3 KO mice examined at 7 dpi. Numbers associated with the bar graph indicate the number of dentate gyri and total number of clones (in parentheses) analyzed, grey bars = WT, blue bars = KO. Values represent mean ± S.E.M. (*P < 0.01; n.s. P > 0.1; AVOVA). e Stronger relative increase of RGL activation in the temporal dentate gryus of adult sfrp3 KO mice. Same groups of animals in Fig. 4d were analyzed. Data were normalized to control WT group
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Fig4: Activation of quiescent radial glia-like neural stem cells increases in adult sfrp3 knockout (KO) mice. a Quantitative analysis of MCM2+nestin+ RGLs along the septo-temporal axis of adult sfrp3 KO and wildtype (WT) littermates. Values present mean ± S.E.M. [n = 6 (KO), 7 (WT)]. b Higher relative increase in RGL activation in the temporal dentate gyrus of adult sfrp3 KO mice. Same groups of animals in Fig. 4b were analyzed. Data were normalized to control WT group from septal (1) to temporal (4) dentate gyrus. c Representative confocal images of immunostaining of GFP (green) for quiescent and activated clones in the adult nestin-CreERT2+/−;Z/EGf/+; sfrp3−/− KO mice and nestin-CreERT2+/−;Z/EGf/+; sfrp3+/+ control mice. Scale bar = 10 μm. d Quantification of increased RGL activation at both septal and temporal poles in the dentate gyrus of adult sfrp3 KO mice examined at 7 dpi. Numbers associated with the bar graph indicate the number of dentate gyri and total number of clones (in parentheses) analyzed, grey bars = WT, blue bars = KO. Values represent mean ± S.E.M. (*P < 0.01; n.s. P > 0.1; AVOVA). e Stronger relative increase of RGL activation in the temporal dentate gryus of adult sfrp3 KO mice. Same groups of animals in Fig. 4d were analyzed. Data were normalized to control WT group

Mentions: Finally, we examined the contribution of the sfrp3 molecular gradient on the differential regulation of quiescent RGL activation along the septo-temporal axis. Although it is impossible to rule out compensatory effects during development from germline transgenic mice, our previous analyses of adult sfrp3 knockout mice did not indicate any gross or cumulative morphological effects on the dentate gyrus [40]. Consistent with our previous population study, sfrp3 knockout mice exhibited increased activation of quiescent RGLs as shown by the increased density of MCM2+ RGLs (Fig. 4a). This increase occurred in both septal and temporal regions and, notably, the magnitude of the change in quiescent RGL activation gradually increased from regions 1 to 3 along the septo-temporal axis, but not in region 4 at the most temporal pole (Fig. 4b). Therefore, removal of sfrp3 expression and its associated gradient dampens, but does not completely abolish, the septo-temporal differences in quiescent RGL activation during adult hippocampal neurogenesis. These results support an active role for the sfrp3 gradient in differential regulation of stem cell activation along the septo-temporal axis, but also point to additional mechanism(s) that may mediate residual differences, particularly in the temporal pole.Fig. 4


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 increases in adult sfrp3 knockout (KO) mice. a Quantitative analysis of MCM2+nestin+ RGLs along the septo-temporal axis of adult sfrp3 KO and wildtype (WT) littermates. Values present mean ± S.E.M. [n = 6 (KO), 7 (WT)]. b Higher relative increase in RGL activation in the temporal dentate gyrus of adult sfrp3 KO mice. Same groups of animals in Fig. 4b were analyzed. Data were normalized to control WT group from septal (1) to temporal (4) dentate gyrus. c Representative confocal images of immunostaining of GFP (green) for quiescent and activated clones in the adult nestin-CreERT2+/−;Z/EGf/+; sfrp3−/− KO mice and nestin-CreERT2+/−;Z/EGf/+; sfrp3+/+ control mice. Scale bar = 10 μm. d Quantification of increased RGL activation at both septal and temporal poles in the dentate gyrus of adult sfrp3 KO mice examined at 7 dpi. Numbers associated with the bar graph indicate the number of dentate gyri and total number of clones (in parentheses) analyzed, grey bars = WT, blue bars = KO. Values represent mean ± S.E.M. (*P < 0.01; n.s. P > 0.1; AVOVA). e Stronger relative increase of RGL activation in the temporal dentate gryus of adult sfrp3 KO mice. Same groups of animals in Fig. 4d were analyzed. Data were normalized to control WT group
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Fig4: Activation of quiescent radial glia-like neural stem cells increases in adult sfrp3 knockout (KO) mice. a Quantitative analysis of MCM2+nestin+ RGLs along the septo-temporal axis of adult sfrp3 KO and wildtype (WT) littermates. Values present mean ± S.E.M. [n = 6 (KO), 7 (WT)]. b Higher relative increase in RGL activation in the temporal dentate gyrus of adult sfrp3 KO mice. Same groups of animals in Fig. 4b were analyzed. Data were normalized to control WT group from septal (1) to temporal (4) dentate gyrus. c Representative confocal images of immunostaining of GFP (green) for quiescent and activated clones in the adult nestin-CreERT2+/−;Z/EGf/+; sfrp3−/− KO mice and nestin-CreERT2+/−;Z/EGf/+; sfrp3+/+ control mice. Scale bar = 10 μm. d Quantification of increased RGL activation at both septal and temporal poles in the dentate gyrus of adult sfrp3 KO mice examined at 7 dpi. Numbers associated with the bar graph indicate the number of dentate gyri and total number of clones (in parentheses) analyzed, grey bars = WT, blue bars = KO. Values represent mean ± S.E.M. (*P < 0.01; n.s. P > 0.1; AVOVA). e Stronger relative increase of RGL activation in the temporal dentate gryus of adult sfrp3 KO mice. Same groups of animals in Fig. 4d were analyzed. Data were normalized to control WT group
Mentions: Finally, we examined the contribution of the sfrp3 molecular gradient on the differential regulation of quiescent RGL activation along the septo-temporal axis. Although it is impossible to rule out compensatory effects during development from germline transgenic mice, our previous analyses of adult sfrp3 knockout mice did not indicate any gross or cumulative morphological effects on the dentate gyrus [40]. Consistent with our previous population study, sfrp3 knockout mice exhibited increased activation of quiescent RGLs as shown by the increased density of MCM2+ RGLs (Fig. 4a). This increase occurred in both septal and temporal regions and, notably, the magnitude of the change in quiescent RGL activation gradually increased from regions 1 to 3 along the septo-temporal axis, but not in region 4 at the most temporal pole (Fig. 4b). Therefore, removal of sfrp3 expression and its associated gradient dampens, but does not completely abolish, the septo-temporal differences in quiescent RGL activation during adult hippocampal neurogenesis. These results support an active role for the sfrp3 gradient in differential regulation of stem cell activation along the septo-temporal axis, but also point to additional mechanism(s) that may mediate residual differences, particularly in the temporal pole.Fig. 4

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