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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

A gradient of sfrp3 expression in dentate gyrus from early postnatal to aged animals. a Representative images of sfrp3 mRNA in situ in the dentate gyrus of wildtype mice at different ages (P7, P10, P56 and P360). Scale bar, 250 μm. b Quantification of signal intensity for sfrp3 in situ, which was performed on the images shown in Fig. 3a. Reconstructed dentate gyri from sagittal sections were divided into 100 bins (represented on the X axis) for quantification of signal intensity along the septo-temporal axis. Values represent mean ± S.E.M. (n = 3). The sfrp3 mRNA expression increases from septal to temporal dentate gyrus at each age from P7 to P56 in WT mice with an increase in slope during the interval of P7-P56
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Fig3: A gradient of sfrp3 expression in dentate gyrus from early postnatal to aged animals. a Representative images of sfrp3 mRNA in situ in the dentate gyrus of wildtype mice at different ages (P7, P10, P56 and P360). Scale bar, 250 μm. b Quantification of signal intensity for sfrp3 in situ, which was performed on the images shown in Fig. 3a. Reconstructed dentate gyri from sagittal sections were divided into 100 bins (represented on the X axis) for quantification of signal intensity along the septo-temporal axis. Values represent mean ± S.E.M. (n = 3). The sfrp3 mRNA expression increases from septal to temporal dentate gyrus at each age from P7 to P56 in WT mice with an increase in slope during the interval of P7-P56

Mentions: Although it is well-known that morphogens act as graded positional cues to control cell fate specification in many developing tissues, the presence of a gradient in adult tissue is very rare. We next investigated the developmental time point when the gradient expression pattern of sfrp3 is established. Previous studies have examined sfrp3 expression during early embryonic development. Specifically, sfrp3 is not expressed in the cortical hem, which is the hippocampal organizer [48], but is instead expressed dorsal to this region at E14.5 and becomes confined to the dentate gyrus at E17.5 [49]. Using in situ hybridization, we examined the magnitude and time course of sfrp3 expression from postnatal day 7 (P7), when the dentate gyrus is recognizable as a morphological structure with two blades of discrete dentate granule cell layers (Fig. 3a). At P7, the sfrp3 in situ signal was scattered in the dentate granule cell layer and CA3. By P10, sfrp3 expression became prominent in the dentate gyrus, although still weaker than in the adult dentate gyrus. The gradient expression pattern was observed at P7, became readily apparent by P10, and persisted at P360 (Fig. 3a). Quantitative analysis showed that the slope of the sfrp3 mRNA expression gradient increased between P7 and P56 (Fig. 3b). Together, these results revealed that the gradient expression pattern of sfrp3 is initiated during early postnatal stages and becomes more pronounced later and maintained during adulthood.Fig. 3


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)

A gradient of sfrp3 expression in dentate gyrus from early postnatal to aged animals. a Representative images of sfrp3 mRNA in situ in the dentate gyrus of wildtype mice at different ages (P7, P10, P56 and P360). Scale bar, 250 μm. b Quantification of signal intensity for sfrp3 in situ, which was performed on the images shown in Fig. 3a. Reconstructed dentate gyri from sagittal sections were divided into 100 bins (represented on the X axis) for quantification of signal intensity along the septo-temporal axis. Values represent mean ± S.E.M. (n = 3). The sfrp3 mRNA expression increases from septal to temporal dentate gyrus at each age from P7 to P56 in WT mice with an increase in slope during the interval of P7-P56
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4559945&req=5

Fig3: A gradient of sfrp3 expression in dentate gyrus from early postnatal to aged animals. a Representative images of sfrp3 mRNA in situ in the dentate gyrus of wildtype mice at different ages (P7, P10, P56 and P360). Scale bar, 250 μm. b Quantification of signal intensity for sfrp3 in situ, which was performed on the images shown in Fig. 3a. Reconstructed dentate gyri from sagittal sections were divided into 100 bins (represented on the X axis) for quantification of signal intensity along the septo-temporal axis. Values represent mean ± S.E.M. (n = 3). The sfrp3 mRNA expression increases from septal to temporal dentate gyrus at each age from P7 to P56 in WT mice with an increase in slope during the interval of P7-P56
Mentions: Although it is well-known that morphogens act as graded positional cues to control cell fate specification in many developing tissues, the presence of a gradient in adult tissue is very rare. We next investigated the developmental time point when the gradient expression pattern of sfrp3 is established. Previous studies have examined sfrp3 expression during early embryonic development. Specifically, sfrp3 is not expressed in the cortical hem, which is the hippocampal organizer [48], but is instead expressed dorsal to this region at E14.5 and becomes confined to the dentate gyrus at E17.5 [49]. Using in situ hybridization, we examined the magnitude and time course of sfrp3 expression from postnatal day 7 (P7), when the dentate gyrus is recognizable as a morphological structure with two blades of discrete dentate granule cell layers (Fig. 3a). At P7, the sfrp3 in situ signal was scattered in the dentate granule cell layer and CA3. By P10, sfrp3 expression became prominent in the dentate gyrus, although still weaker than in the adult dentate gyrus. The gradient expression pattern was observed at P7, became readily apparent by P10, and persisted at P360 (Fig. 3a). Quantitative analysis showed that the slope of the sfrp3 mRNA expression gradient increased between P7 and P56 (Fig. 3b). Together, these results revealed that the gradient expression pattern of sfrp3 is initiated during early postnatal stages and becomes more pronounced later and maintained during adulthood.Fig. 3

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