A septo-temporal molecular gradient of sfrp3 in the dentate gyrus differentially regulates quiescent adult hippocampal neural stem cell activation
- Jiaqi Sun†1, 2,
- Michael A. Bonaguidi†2, 3, 8,
- Heechul Jun4,
- Junjie U. Guo2, 3, 9,
- Gerald J. Sun2, 5,
- Brett Will2,
- Zhengang Yang6,
- Mi-Hyeon Jang4,
- Hongjun Song2, 3, 5,
- Guo-li Ming2, 3, 5, 7Email author and
- Kimberly M. Christian2, 3
© Sun et al. 2015
Received: 22 February 2015
Accepted: 25 August 2015
Published: 4 September 2015
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.
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.
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.
Along with its well-known role in learning and memory, the hippocampus is a neural structure involved in the regulation of motivational behaviors, emotional states and stress responses [1, 2]. The rodent hippocampus is an elongated, laminated structure with its long axis extending rostro-dorsally from the septal nuclei of the basal forebrain, over and behind the thalamus, and then caudo-ventrally to the temporal lobe. This longitudinal axis of the hippocampus is usually referred to as the septo-temporal (or dorso-ventral) axis [3, 4]. Differences in anatomical connections and electrophysiological properties along the septo-temporal axis of the hippocampus have been well documented [5–11]. In addition, studies using targeted lesions and inactivation have revealed functional differences along this hippocampal axis. Specifically, the septal (dorsal) portion appears to be preferentially engaged in learning and memory processes associated with navigation and exploration, while the temporal (ventral) hippocampus appears to be more involved in mood and anxiety-related behaviors [12, 13]. Consistent with these findings, a recent study has demonstrated that acute activation of granule cells specifically in the dorsal or ventral hippocampal dentate gyrus differentially suppresses contextual learning or innate anxiety, respectively . Moreover, region-specific gene expression supports segregation of the hippocampus into septal, intermediate and temporal zones [11, 15].
The adult mammalian hippocampus continuously generates new neurons that integrate into preexisting neuronal networks [16–18]. Adult neurogenesis is a complex process whereby quiescent radial glia-like neural stem cells (RGLs) give rise to newborn neurons that mature over several weeks [16–19]. Cumulative evidence suggests that several properties of adult neurogenesis vary throughout the longitudinal (septo-temporal) axis of the hippocampus. The magnitude of adult hippocampal neurogenesis is lower in the temporal region, as assessed by the number of RGLs, intermediate progenitor cells and immature neurons [20, 21]. The pace of neurogenesis is also slower in the temporal region, but it appears to be more responsive to local niche dynamics and exogenous factors . Not only can changes in neuronal activity alter the tempo of newborn neuron maturation more dramatically, but the age-related decline in precursor number occurs more rapidly in the temporal dentate gyrus [22–24]. Furthermore, studies indicate a functional dissociation for adult hippocampal neurogenesis along the longitudinal axis wherein newborn neurons in the dorsal dentate gyrus modulate learning of contextual discrimination under some conditions, while immature neurons in the ventral dentate gyrus mediate anxiolytic effects of the anti-depressant fluoxetine . How these differences in neurogenesis along the longitudinal axis of hippocampus are regulated is a fundamental question that remains to be answered.
Morphogens and their expression gradients play an essential role in the patterning of organogenesis during embryonic development . Among these, Wingless/INT (Wnt) family members are critical morphogens that regulate numerous developmental processes, including neural stem cell maintenance and differentiation in the vertebrate central nervous system (CNS) [27, 28]. During embryonic and early postnatal development, Wnt signaling is essential for the proper formation of the hippocampus. For example, Wnt3a is expressed in the cortical hem, which serves as a signaling center for hippocampal development at the tip of the caudomedial cortical wall, and is crucial for the normal growth of the hippocampus . Furthermore, fate specification is determined by the relative strength of Wnt signaling such that strong Wnt signaling biases differentiation toward a dentate granule cell fate, while moderate Wnt signaling specifies pyramidal cells of the cornus ammonis (CA) layers . In the dentate gyrus of the adult mouse hippocampus, many Wnts and their inhibitors are expressed  and functional studies have revealed that Wnt signaling regulates multiple steps of adult hippocampal neurogenesis under different physiological conditions [32–39]. In particular, we recently showed that mature granule cells in the adult mouse dentate gyrus express secreted Frizzled-related protein 3 (sfrp3), a secreted inhibitor of Wnt signaling, and that deletion of sfrp3 leads to increased activation of quiescent RGLs and production of new neurons , as well as behaviors mimicking those observed with long-term antidepressant treatment . In this study, we examined whether sfrp3 could contribute to differences in the magnitude of adult hippocampal neurogenesis along the septo-temporal axis.
Heterogeneity of quiescent RGL activation along the septo-temporal axis of adult mouse dentate gyrus
A gradient of sfrp3 expression along the septo-temporal axis of the adult dentate gyrus
Developmental establishment of the sfrp3 expression gradient in the dentate gyrus
Functional impact of sfpr3 gradient on neurogenesis along the septo-temporal axis
To further support our model, we examined quiescent RGL activation using an independent approach via clonal lineage-tracing of individual quiescent RGLs. We previously established a clonal assay in which we could label individual quiescent RGLs in adult nestin-CreER T2+/− ;Z/EG f/+ mice with injection of a single low dose of tamoxifen to quantify their activation rates and fate choices [32, 41, 45]. We generated adult nestin-CreER T2+/− ;Z/EG f/+ ; sfrp3 −/− and nestin-CreER T2+/− ;Z/EG f/+ ; sfrp3 +/+ mice and performed short-term clonal analysis. We quantified quiescent (an isolated RGL) or activated (an RGL with one or more progeny in close proximity) individual clones with respect to their septal or temporal localization in the dentate gyrus (Fig. 4c), which indicated the cumulative RGL activation during the testing period. Consistent with previous studies , sfrp3 knockout mice exhibited an increase in the number of activated RGLs throughout the hippocampus (Fig. 4d). Notably, the increase in RGL activation is more than doubled in the temporal region compared to that in the septal region (Fig. 4e). These results also support our model that the graded sfrp3 expression along the longitudinal hippocampal axis contributes to the regional differences in RGL activation rates.
In the developing brain, morphogen gradients are commonly used to pattern neurogenic regions into distinct functional domains. Examples of such gradients are WNTs that are responsible for specifying dorsal fates during telencephalic neurogenesis . Several members of the Wnt family (including Wnt-2b, Wnt-3a, Wnt-5a, Wnt-7b, and Wnt-8b), as well as members of the SFRP family of Wnt inhibitors, are highly expressed in the cortical hem, a medial telencephalic signaling center, which is also the primary hippocampal organizer [28, 51]. Gradients of Wnt family members are well studied in the developing hippocampus . Whether any of these gradients persist into adulthood was not previously known. Early in development, sfrp3 is expressed weakly in the medial neuroepithelium and medial non-neural mesenchyme, but is excluded from the cortical hem. Later, sfrp3 is expressed in cells from the dentate notch to the developing dentate gyrus along the migratory route of newly born dentate granule cells and their precursors. In addition, sfrp3 is expressed in the tertiary matrix, which is the displaced mitotic zone that transiently forms at the termination of this migratory route in the hilus of the dentate gyrus . Here we identified a graded expression pattern of sfrp3 that emerges by postnatal day 7. Our study revealed, for the first time, that a morphogen-related protein gradient is generated postnatally and maintained in the adult mammalian brain.
The proliferation and integration of adult-born neurons into existing hippocampal circuitry has been implicated in a wide range of behaviors, including context discrimination, pattern separation, spatial learning, anxiety, and responses to antidepressants [18, 52–57]. These diverse functions may reflect differences in the local hippocampal network along the septal-temporal axis, with respect to anatomical connections and electrophysiological properties. For example, serotonergic fibers provide denser input to the temporal hippocampus with a concomitant enrichment of 5-HT1A and 2C receptors [10, 58]. Long-term potentiation (LTP) is both larger and longer lasting in septal slices . Growing evidence supports that adult neurogenesis in the dentate gyrus is also heterogeneous along this longitudinal axis. A higher number of proliferating cells and faster maturation rates occur in the septal dentate gyrus compared to the temporal region . Because adult neurogenesis has been implicated in both cognitive and affective behaviors, an exciting possibility is that adult-born granule cells in the septal and temporal hippocampus may be functionally dissociated . However, little was known about potential niche mechanisms that could contribute to septo-temporal heterogeneity in hippocampal neurogenesis processes and properties. Our study identifies a gradient of expression of sfrp3 (inferred from its mRNA levels), a niche factor secreted by mature dentate granule neurons, that results in differential control of neurogenesis along the longitudinal axis of the dentate gyrus. Both population analysis and in vivo clonal analysis, using a genetic sparse-labeling approach, indicate that removal of sfrp3 and its gradient result in preferentially increased RGL activation in the temporal dentate gyrus. Since higher levels of sfrp3 are expressed under physiological conditions in this region, our results functionally link neural stem cell activity to specific patterns of gene expression.
Our previous study identified sfrp3 as a neuronal activity-regulated niche factor that exhibits control over multiple steps of adult hippocampal neurogenesis, including progenitor proliferation, newborn neuron maturation, dendritic growth and dendritic spine formation, as well as the activation of quiescent adult neural stem cells . Sfrp3 is an essential mediator of some antidepressant actions in animal models and polymorphisms in the human gene are significantly associated with partial antidepressant responses in patients, which suggest that manipulation of SFRP3 action may represent a novel therapeutic approach to treat depression . Here, we reveal higher expression levels of sfrp3 in the temporal hippocampus, which is the region more actively involved in mediating affective behaviors. Our study thus suggests how SFRP3 could be an efficacious and highly restricted extracellular target for fine-tuning adult hippocampal neurogenesis in a region-specific manner. Taken together, our results reveal a molecular gradient generated by local mature dentate granule neurons that couples adult neurogenesis to heterogeneities in the surrounding niche. This gradient provides a mechanism that may contribute to regional differences in adult neurogenesis and parallels the functional differences along the septo-temporal axis. As several genes have recently been reported to be differentially expressed and regulated along the septo-temporal axis of the hippocampus [11, 15], sfrp3 may be one of multiple molecular gradients contributing to heterogeneous functional properties of the hippocampus through regulation of neural stem cell activation, neuronal development and circuit integration during adult neurogenesis.
We found that sfrp3, a secreted inhibitor of Wnt signaling, is expressed in a gradient along the septo-temporal axis of the dentate gyrus that is established during postnatal development. We provide functional evidence that this molecular gradient regulates quiescent RGL activation. Our study thus demonstrates, for the first time, a molecular niche mechanism to support region-specific differences in adult hippocampal neurogenesis along the longitudinal axis of hippocampus.
Materials and methods
Animals, housing, administration of tamoxifen and tissue processing
Eight-week-old mice of the following genotypes were used: wild-type (C57BL/6), sfrp3 wild-type (WT) and knockout (KO) (B6;129), nestin-CreER T2+/− ;Z/EG f/+ ; sfrp3 −/− (C57BL/6) and nestin-CreER T2+/− ;Z/EG f/+ ; sfrp3 +/+ (C57BL/6). Animals were housed in the standard facility. All animal procedures used in this study were performed in accordance with the protocol approved by the Institutional Animal Care and Use Committee.
A single low dose of tamoxifen (62 mg/kg body weight, i.p.; Sigma) in 2-month-old mice resulted in sparse labeling at the clonal level for analysis at 7 dpi in both WT and sfrp3 KO mice, as previously described . Mice were anaesthetized (100 μg ketamine, 10 μg xylazine in 10 μl saline per gram) and perfused with 4 % paraformaldehyde (PFA) and brains were postfixed in PFA overnight. Brains were then transferred to 30 % sucrose and stored at 4 °C until brains sank to the bottom of tube.
Anatomical definitions and sectioning
For analysis of neurogenesis along the longitudinal axis, the right hippocampus was dissected and sectioned perpendicular to its long axis to enable comparable analyses along the entire axis. This axis is most precisely described as the septo-temporal axis (Fig. 1a). Sections were cut at 40 μm using a cryostat (Leica CM 3050S) for a total of ~80 sections. Every sixth section was collected and processed for immunostaining.
For clonal analysis, coronal brain sections (40 μm) through the entire dentate gyrus were collected in a serial order for a total of ~50 sections using a microtome (Leica SM 2010R), which is along the anterior-posterior axis.
Immunostaining, confocal imaging, in situ hybridization and quantitative real-time reverse transcription PCR
For immunostaining with anti-nestin and anti-MCM2, an antigen retrieval protocol was performed by microwaving sections in boiled citric buffer for 7 min as described previously . Immunostaining was performed with the following primary antibodies: anti-GFP (Rockland; goat; 1:500 dilution), anti-nestin (Aves; chick; 1:500 dilution), anti-MCM2 (BD; mouse; 1:500 dilution). Images were acquired on a Zeiss LSM 710 confocal system (Carl Zeiss) with a × 40 objective lens using a multitrack configuration.
In situ hybridization analysis was performed similarly as previously described . Briefly, 4 % paraformamide-fixed cryo-protected brain tissue samples were embedded in O.C.T. mounting solution and frozen at −80 °C. Brain sections (20 μm) were cut onto Superfrost-Plus slides (Fisher Scientific). Full-length digoxygenin-labeled antisense riboprobe for sfrp3 was prepared by in vitro transcription. Sections were hybridized with the riboprobes at 65 °C overnight, and washed once in 5X SSC and 1 % SDS, then twice in 2X SSC without SDS for 30 min each at 65 °C. After overnight incubation with alkaline phosphatase-conjugated anti-digoxygenin antibody at 4 °C, hybridized riboprobes were visualized using nitro blue tetrazolium (NBT, 35 μg/ml)/5-bromo-4-chloro-3-indolyl phosphate (BCIP, 18 μg/ml) color reaction at room temperature.
For quantitative real-time reverse transcription PCR, dentate gyrus tissue was rapidly micro-dissected from adult WT mice and cut into three fragments (septal, intermediate and temporal regions). For gene expression analysis, the total RNA fraction was immediately isolated after dissection (Qiagen), treated with DNAase and reverse-transcribed into the first-strand cDNA (Invitrogen). Specific primers as followed were used in SYBR-green based quantitative real-time PCR to measure the expression level of target genes with the ∆∆Ct method (ABI).
GAPDH: 5’- GTATTGGGCGCCTGGTCACC-3’ (forward), 5’- CGCTCCTGGAAGATGGTGATGG-3’ (reverse); sFRP3: 5’- CAAGGGACACCGTCAATCTT-3’ (forward), 5’- CATATCCCAGCGCTTGACTT-3’ (reverse).
Quantification and statistical analysis
For quantification of signal intensity of in situ hybridization on hippocampal coronal sections, brightfield images were taken at the same exposure and converted into grey scale. Granule cell layers of dentate gyrus were circled and mean grey values were obtained. For normalization, an area without signal was selected and mean grey values were calculated. The intensity indicated by the mean grey values in the granule cell layer after subtracting the mean grey value in the area without signal represents the relative expression levels. For quantification of signal intensity of in situ hybridization in hippocampal sagittal sections, brightfield images were manually segmented in LSM image browser (Zeiss) using the 'closed free shape curved drawing' and the 'extract region' tools. Segmented dentate gyri were then manually aligned using Reconstruct  and rotated such that the dentate gyrus occupied a maximum horizontal space. Aligned images were loaded as matrices into Matlab (Mathworks) for quantitative measurements. Matrices were summed across rows and the resulting vector was divided into 100 bins. The mean value for each bin was calculated and the resulting 100 mean values were used as the quantitative expression data across the dentate gyrus for each analyzed image.
For quantification of MCM2+ RGLs, an inverted ‘Y’ shape from anti-nestin staining superimposed on MCM2+ nucleus was scored double positive for nestin and MCM2, as described previously . All analyses were performed by investigators blind to experimental conditions. Statistical significance (p < 0.01) was assessed with a one-way ANOVA or Student’s t test, as indicated.
We thank members of the Song and Ming laboratories for their suggestions, A. Rattner and J. Nathans for generating sfrp3 KO mice, K. Liu for help with in situ hybridization. This work was supported by the NIH (NS047344 and NS093772 to H.S; NS048271 and MH105128 to G.M.; MH090115 to M.-H.J.; and NS080913 to M.A.B) and NARSAD (to K.M.C., G.M. and H.S.).
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
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