BMB Reports 2024; 57(4): 182-187  https://doi.org/10.5483/BMBRep.2023-0149
ErbB3 binding protein 1 contributes to adult hippocampal neurogenesis by modulating Bmp4 and Ascl1 signaling
Youngkwan Kim1,2 , Hyo Rim Ko1,2 , Inwoo Hwang1,2 & Jee-Yin Ahn1,2,3,*
1Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 16419, 2Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon 16419, 3Samsung Biomedical Research Institute, Samsung Medical Center, Seoul 06351, Korea
Correspondence to: Tel: +82-31-299-6134; Fax: +82-31-299-6029; E-mail: jeeahn@skku.edu
Received: August 21, 2023; Revised: August 30, 2023; Accepted: September 28, 2023; Published online: January 18, 2024.
© Korean Society for Biochemistry and Molecular Biology. All rights reserved.

cc This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Neural stem cells (NSCs) in the adult hippocampus divide infrequently; the endogenous molecules modulating adult hippocampal neurogenesis (AHN) remain largely unknown. Here, we show that ErbB3 binding protein 1 (Ebp1), which plays important roles in embryonic neurodevelopment, acts as an essential modulator of adult neurogenic factors. In vivo analysis of Ebp1 neuron depletion mice showed impaired AHN with a low number of hippocampal NSCs and neuroblasts. Ebp1 leads to transcriptional repression of Bmp4 and suppression of Ascl1 promoter methylation in the dentate gyrus of the adult hippocampus reflecting an unusually high level of Bmp4 and low Ascl1 level in neurons of Ebp1-deficient mice. Therefore, our findings suggests that Ebp1 could act as an endogenous modulator of the interplay between Bmp4 and Ascl1/Notch signaling, contributing to AHN.
Keywords: Adult hippocampal neurogenesis, Ascl1, Bmp4, ErbB3 binding protein 1, Stem cells
INTRODUCTION

Neurogenesis occurs in two neurogenic niches of the brain, the dentate gyrus (DG) of hippocampus and in the subventricular zone (SVZ) adjacent to the lateral ventricles throughout the entire life (1). In these niches, new neurons are continuously generated from the Sry-related high mobility group box transcription factor (Sox2)-expressing undifferentiated cells and stem cells. However, Sox2+ cells miss the proliferative capacity in rodents upon their growth (2, 3), suggesting that the number of cycles of adult NSCs is limited. These findings emphasize a potent role of quiescence state of NSC to maintain the regenerative potential of the DG. Among the signal transduction pathways governing stem cells across their phylogeny, bone morphogenetic proteins (BMPs), are key regulators of stem cell self-renewing divisions and maintenance in a rage of niches (4, 5), modulating NSC function (6-9). BMPs diminish proliferation of cultured NSCs while maintaining their undifferentiated state. In vivo, acute blockade of BMP signaling in the hippocampus by intracerebral Noggin infusion recruits quiescent NSCs into the cycle and accelerate neurogenesis; before leading to suppress stem cell division and deprivation of precursors and newborn neurons (10). Moreover, transcription factors regulate stem cell dynamics and reprogramming. For example, Ascl1 (also known as Mash1), a basic helix loop helix transcription factor that plays a pioneer role in neuronal differentiation, acts to balance progenitor and differentiation states in counter to Notch signaling (11), acting as a critical factor in converting fibroblasts into functional neurons in vitro (12). In addition, Ascl1 give cells long-term neurogenic potential in stem cell niche in the adult mouse brain (13). Despite the decline in AHN with age (14, 15), neurogenesis persists throughout adulthood (16); thus, it is essential to understand how NSCs establish the balance of their self-renewal and differentiation in vivo for demonstration of the intrinsic factors that define NSC populations; moreover, restoration of neural precursors with potential to form new neurons is an attractive prospect for replacement therapy in neurodegenerative diseases.

Ebp1 is a critical controller of the cell cycle, neuronal survival, differentiation, as well as axon growth and regeneration after injury (17), contributing to gene expression, epigenetic control, and translational regulation as well as protein-protein interactions. Two isoforms of Ebp1 p48 and p42 (lacking 54 amino acids at the N-terminus compared to p48) have been known with distinctive functions in certain types of cancers; p48 Ebp1 is the major isoform in neurons in the developing brain, while p42 Ebp1 is no detectable in the embryogenesis (18). In human embryonic stem cells, developmental pluripotency-associated 4 (DPPA4) only interact with p48 EBP1 but not p42 and this interaction reduced upon differentiation of pluripotent cells. However, in mouse ESCs, DPPA4 binds to transcriptionally active chromatin, associating with phosphorylated RNA polymerase II and H3K4 trimethylation (19). DPPA4 causes transcriptional repression whereas EBP1 inhibits its effects, promoting stem cell-related transcriptional regulation at specific genomic loci or co-operating in transcriptional activation at native targets (20). In addition, Ebp1 mRNA levels are detectable from E12.5 (21) and increase during the embryonic development in the mouse brain (22). Moreover, Ebp1 silencing leads to neuronal loss, causing dysregulation of epigenetic controllers, such as Suv39H1/DNMT1, and/or resulting in transcriptional dysregulation in the development and disease (22-24). Considering that Ebp1 regulates transcriptional controller during embryonic neural development, Ebp1 might contribute to adult neurogenesis by modulating transcriptional/epigenetic control.

Here, we present in vivo evidence for an important function of Ebp1 for transcriptional/epigenetic control during AHN. Genetic ablation of Ebp1 in neurons causes brain atrophy with neuron loss and dysregulation of Bmp4 , and Ascl1, accessing closed chromatin to allow other factors to bind and activate neural pathways. While neuronal Ebp1 depletion revealed a dramatic reduction of neurons along with DCX+/Sox2+ NSCs in the DG, reintroduction of AAV2-Ebp1 into an ex vivo organotrophic slice culture model of the hippocampus significantly increased neuronal nuclei (NeuN) positive neurons. Taken together, our findings suggest the Ebp1 contributes to AHN by controlling Bmp4 and Ascl1 axis in the DG.

RESULTS

Neuronal Ebp1 depletion causes brain atrophy and neuron loss

Ebp1 expressed in the mouse hippocampus of postnatal day 30 was abundant not only in CA1–CA3 regions but also in the DG, where new neurons are generated (Fig.1A), suggesting the possibility that Ebp1 may be involved in adult neurogenesis. To clarify its role in AHN, we used neuron Ebp1 knock out mice, Ebp1-CKO (hereafter Ebp1-CKO) generated by crossing Ebp1 conditional knock out (Ebp1flox/flox) mice with a Nestin-Cre driver (22). Compared to control mice, Ebp1-CKO showed a decreased hippocampus area at 3 months and decreased cortex thickness in aged mice (14 months) (Fig. 1B, C). Accordingly, our immunohistochemistry (IHC) analysis demonstrated that NeuN+ neurons were more reduced in the brain of Ebp1- CKO mice than in the control mice, indicating that Ebp1 loss causes notable neuron loss in the brain of adult mice (Fig. 1D, Supplementary Fig. 1). Moreover, another neuronal marker, βIII-tubulin (Tuj1) indicated that positive hippocampal neurons are impaired in the primary cultured hippocampal neurons from Ebp1-CKO (Fig. 1E).

Impaired AHN in the DG of Ebp1-CKO mice

To determine AHN’s role in case of neuronal Ebp1 loss, we measured the proliferative rate in the DG by BrdU incorporation in both 4- and 12-month-old Ebp1-CKO and control mice. Anti-BrdU staining of brain sections encompassing the entire hippocampus, revealed fewer BrdU+ cells in the DG of Ebp1-CKO mice, indicating reduced proliferation of the resident neuronal progenitors (Fig.2A). The expression of progenitor and neuroblast markers, such as Sox2 and Doublecortin (DCX), was analyzed by immunofluorescence. Both at 4- and 12- month-old, the number of Sox2+ cells in the DG were significantly decreased (Fig. 2B). The population of DCX+ cells, representative in the subgranular layer in the control brain, was evidently decreased in the DG of Ebp1-CKO (Fig. 2C), suggesting that Ebp1 depletion affects the early stage of production of progenitor cells and consequently decreasing neuroblast generation.

To confirm that AHN impairment in Ebp1-CKO was due to lack of Ebp1 and the role of Ebp1 in neurogenesis, we generated adeno-associated virus 2 (AAV2) expressing GFP-Ebp1 or GFP-mock and performed ex vivo infection into an organotrophic hippocampal slice culture model (Fig. 2D). The success of the adenoviral delivery was verified via GFP expression; NeuN+ neurons prominently increased in the brain of Ebp1-CKO mice expressing AAV2-GFP-Ebp1, whereas the brain of Ebp1-CKO mice expressing AAV2-GFP-mock exhibited a largely reduced NeuN intensity (Fig. 2E). Thus, our data demonstrated that upon deletion of neuronal Ebp1, AHN is impaired in the DG.

Ebp1 deficiency aggravates proliferation and differentiation of adult NSCs

To examine the physiological effect of Ebp1 in NSCs, we evaluated the proliferative and differentiative properties of neural progenitors derived from the adult DG of hippocampus of 2-month-old Ebp1-CKO and control mice, grown as neurosphere cultures. The primary neurospheres obtained from Ebp1-CKO displayed dramatically less Sox2+ progenitors, suggesting proliferative defects of DG progenitors (Fig. 3A). In addition, the overall numbers of primary neurospheres obtained from Ebp1- CKO were notably lower than those from control mice and their size was much smaller (the number of stem cells/mouse: Ebp1-CKO 1.9 ± 1.1; control 7.8 ± 1.7), (average diameter of neurospheres: Ebp1-CKO 16.2 ± 7.7; control 159.0 ± 30.8) (Fig. 3B, C).

After exiting the cell cycle, immature neuroblasts go through differentiation before fully maturing (16). In rodents, DCX expression occurs during most AHN differentiation stages and most DCX+ cells acquire a dentate granule cell (DGC) fate, allowing using it as a marker of immature DGCs (25). Therefore, we examined whether Ebp1 silencing could interrupt the neuronal differentiation of neuroblasts. Isolated NSCs were cultured to differentiate to neuroblasts in differentiation medium under treatment with siRNA-Ebp1 or scramble control. While control treated NSCs successfully differentiated to DCX+ neurons, siRNA-Ebp1 treated cells revealed impairment of neuronal differentiation of DCX+ cells, with much shorter neurites upon Ebp1 inhibition (Fig. 3D). Accordingly, neural progenitors isolated from the DG of Ebp1-CKO exhibited impaired neuron morphology: lower complexity with shorter neurites, indicating less differentiation capacity of DCX+ neurons (Fig. 3E). Therefore, our data suggest that Ebp1 is critical for neural progenitor proliferation and neuroblast differentiation.

Ebp1 depletion causes defective transcription of genes important for AHN

To understand the molecular mechanism whereby Ebp1 regulates AHN, we made a transcriptome profiling of Ebp1 deficient and control mice. Among the differentially expressed gene profiles, we noticed alteration to genes whose expression was closely associated with neurogenesis (Fig. 4A and Supplementary Fig. 2). Specifically, the level of Bmp4, a critical regulator of neurogenesis, was highly upregulated whereas that of Ascl1, a transcription factor involved in neuronal differentiation, was downregulated in the absence of Ebp1. Accordingly, qRT-PCR of these genes from RNA isolated from control and Ebp1-CKO mice showed a remarkable increase of Bmp4 and a reduction of Ascl1 (Fig. 4B) levels. Moreover, overexpression of Ebp1-WT in hippocampal HT22 cells inhibited Bmp4 expression and augmented Ascl1 expression (Fig. 4C), suggesting that Ebp1 could affect Bmp4 and Ascl1 gene expression.

As the Bmp4 promoter region possesses a motif for Ebp1 binding (Fig. 4D), we attempted to test whether Ebp1 regulates Bmp4 expression. In our chromatin immunoprecipitation (ChIP) assay using the promoter region of Bmp4 (-1145/-601), when Ebp1 FL was present, RNA polymerase II bound less to the Bmp4 promoter region, whereas promoter binding increased in absence of the winged helix DNA Ebp1 binding domain (Ebp1 ΔWH), indicating that Ebp1 directly binds to the promoter region of Bmp4, inhibiting its transcription (Fig. 4E). To ensure the functional association of Ebp1 to Bmp4 gene regulation, we constructed a mutant Bmp4 promoter luciferase reporter (containing the −1092 to −276 promoter sequence), where the putative Ebp1 binding sequence (around −880 [TACCA]) was mutated by a randomized sequence (GCGTG). As expected, Ebp1 suppressed WT promoter activity. However, with the mutant promoter Ebp1 overexpression did not interfere with its promoter activity, suggesting that this sequence is crucial for Ebp1 to meditate transcriptional repression (Fig. 4F).

In contrast to the Bmp4 upregulation observed in the absence of Ebp1, Ascl1 expression was downregulated. As Ebp1 deficiency resulted in upregulation of DNA (cytosine-5)-methyltransferase (Dnmt1), which represses gene expression by methylation of the promoter of its target genes, we wondered whether the suppressed Ascl1 gene expression reflects promoter methylation in the absence of Ebp1. Without Ebp1, DNMT1 was associated with the Ascl1 promoter, while the RNA polymerase II was notably weakly associated with this promoter compared to the WT (Fig. 4G). Using a DNA methylation analysis, we found enhanced CpG methylation in the absence of Ebp1, reflecting that Ebp1 deficiency resulted in the suppression of Ascl1 expression by promoter methylation (Fig. 4H). Conversely, Ebp1 FL enhanced the promoter activity of Ascl1, whereas Ebp1 ΔWH did not affect the promoter activity of a Ascl1-promoter luciferase reporter (Fig. 4I). Thus, our data suggest that Ebp1 acts as a critical transcriptional/epigenetic controller during AHN, leading to transcriptional suppression of Bmp4 and inhibition of Ascl1 promoter methylation.

DISCUSSION

Neuronal signalings from the niche or transcriptional regulation of neurogenic factors are proposed to control many aspects of NSC behavior, such as balancing the quiescent and proliferative properties of NSCs (to regulate the neurogenesis rate), determining the cell division mode (to maintain the NSC pool), and preventing the premature loss of stem cells or the miss of their properties, to preserve neurogenesis through life (5, 26). The blockade of homeostatic influence of neurogenic niches to NSCs is able to generate pathological results as like cell aging (27). Thus, understanding neurogenic signals could shed light on how adult neurogenesis is controlled and propose a key to successful NSC-mediated regenerative functional recovery.

The importance of Ebp1 in embryonic neural development led us to determine its role in adult neurogenesis. In the current study, we showed that neuronal depletion of Ebp1 in Ebp1-CKO mice resulted in brain atrophy with impeded AHN. These defects could be due in part to deficits in production of neural progenitors and failure of differentiation into neuroblasts (Fig. 2). Particularly, we suggest that an important role for Ebp1 in the neurogenesis is Bmp4 repression. In neuronal Ebp1-deficient mice, we observed an unusual high level of Bmp4, which might imbalance NSC proliferation and differentiation. In addition, we suggest a role of Ebp1 in the epigenetic control of the transcription factor Ascl1 to relieve from DNMT1-mediated Ascl1 methylation, which could contribute to maintain the neurogenic potential of NSCs (Figs. 3 and 4).

BMPs are required to balance NSC quiescence/proliferation and prevent the stem cell activity loss that supports continuous neurogenesis in the mature hippocampus (10); further, BMP-mediated signaling via Smad4 is required to initiate neurogenesis from adult NSCs (8). On the other hand, Ascl1 is involved in the timing of neuronal differentiation, balanced by Notch signaling (28, 29); Ascl1 is present in neural progenitor cells with long-term neurogenic potential in the adult hippocampus (13). A previous study showed that blockade of BMP signaling in the hippocampus first stimulates proliferation, before resulting in loss of the regenerative capacity of the radial stem cell population (10). Thus, it might be possible to maintain NSC populations, while Ebp1 represses Bmp4 meanwhile it activates Ascl1 expression. As a transcriptional repressor of Bmp4 and epigenetic regulator of Ascl1 activation, Ebp1 may reflect the interplay between Bmp4 and Ascl1 with Notch signaling to regulate the dynamic equilibrium between stem cell maintenance and differentiation. This should be further evaluated in Ebp1-CKO mice with Bmp4 or Ascl1-CKO mice.

As alterations in AHN were detected at early stages of the neurodegenerative disease, early therapeutic strategies to evaluate the numbers and functionality of NSC are important to prevent progression of neurodegenerative disease. Here, we propose that Ebp1 could be potential molecule to promote neurogenesis and therapeutic approach to restore neurological disease, suggesting the possibility that Ebp1 acts as an intraneuronal inhibitor of Bmp4. Understanding the interplay between the BMP pathway and other signaling pathways such as the Ascl1/Notch axis may be crucial to understanding the balance of adult NSC division. Among the endogenous molecules expressed in the rodent DG and reported to regulate hippocampal NSCs, Ascl1 may be relevant. Given the antagonistic function of BMP in mediating the development of some central nervous system structures and the role of the fine-tuned activity of the BMP and Ascl1-Notch pathways in the switch from stem cell quiescence to active proliferation in several adult brain (30-32), future attempts should be made to understand the function of Ebp1 in a BMP4 and Ascl1/Notch signaling in a context-dependent manner.

MATERIALS AND METHODS

Animals

Ebp1-CKO mice were generated in collaboration with genOway (Lyon, France). All experimental protocols were performed in accordance with the regulations of the Institutional Animal Care for Ethics and Use Committee of Sungkyunkwan University (SKKUIACUC-2022-02-27-1).

Additional materials and methods are available in the supplementary sections.

ACKNOWLEDGEMENTS

This work was supported by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute and Korea Dementia Research Center, funded by the Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea (grant number: HU21C0157) to J-Y. Ahn.

CONFLICTS OF INTEREST

The authors have no conflicting interests.

FIGURES
Fig. 1. Ebp1 depletion impairs adult stem cell proliferation and differentiation in subgranular zone. (A) IHC staining from the DG of control or Ebp1-CKO mice (n = 4) at 4- or 12-month-old with BrdU (green) and Ebp1 (red) antibodies. (B) IHC staining from the DG in control or Ebp1-CKO mice (n = 3) at 4- or 12-month-old with Sox2 (green) and Ebp1 (red) antibodies. (C) IHC staining from the DG of control or Ebp1-CKO mice (n = 3) at 4- or 12-month-old with DCX (green) and Ebp1 (red) antibodies. Scale bar: 100 μm. (D) Slices were infected with AAV2-GFP-mock or AAV2-GFP-Ebp1 at DIV1 and cultured for 13 additional days before fixation. (E) Representative imaging of slices stained with NeuN (red). Scale bar: 200 mm. Data represent the mean ± SD of indicated numbers of independent experiments. ***P < 0.005, ****P < 0.001 versus control.
Fig. 2. Ebp1-CKO mice show defective neuron formation in the hippocampus. (A) Representative imaging of slices stained with NeuN (green) and Ebp1 (red) antibodies. White boxes indicate the EC, CA1, CA3 and DG region in the hippocampus. Scale bars: 200 or 100 μm. (B) Nissl-stained coronal sections of the hippocampus in control or Ebp1-CKO mice (n = 3) at 3 months. Scale bars: 1 mm. (C) Coronal sections of control or Ebp1-CKO mice (n = 3) stained with Cresyl violet at 14 months. Scale bars: 0.5 mm. (D) IHC staining with NeuN (green) and Ebp1 (red) in the DG from control or Ebp1-CKO mice (n = 3) at 2 months. Scale bar: 100 μm. (E) Representative image of primary hippocampal neurons (n = 3) stained with Tuj1 (green) antibodies. Scale bars: 100 or 50 μm. Data represent the mean ± SD of indicated numbers of independent experiments. **P < 0.01, ***P < 0.005.
Fig. 3. Ebp1 ablation reduces NSC proliferation and differentiation. (A) Representative images of neurospheres stained with Sox2 (green) and Ebp1 (red) antibodies. Relative fluorescence intensity profiles of Sox2 and Ebp1 in neurospheres. Scale bar: 100 μm. (B) Quantification of the number of NSCs (n = 6) at DIV1. (C) Quantification indicates the size of NSCs (n = 6) at passage 10. (D) Representative imaging of neuroblasts (n = 3) stained with DCX (green) and Ebp1 (red) antibodies. Scale bar: 20 μm. (E) Immunocytochemistry staining with DCX (green) and Ebp1 (red) antibodies of differentiated neuroblasts from control or Ebp1-CKO mice (n = 6) at 2 months. Scale bar: 100 μm. Data represent the mean ± SD of indicated numbers of independent experiments. ****P < 0.001.
Fig. 4. Ebp1 affects NSC proliferation and differentiation by regulating neurogenesis-related genes. (A) Volcano plot of RNA-sequencing data showing differential expression of neurogenesis- and cell differentiation-related factors in the hippocampus of Ebp1-CKO (Ebp1flox/flox crossing with a CamKII-Cre) compared with control (Ebp1flox/flox) at 10 months. (B) Quantitative RT-PCR analysis of neurogenesis-related genes from Ebp1-CKO or control hippocampi (n = 3) at 10 months. (C) mRNA expression of Ebp1, Bmp4, and Ascl1 in HT22 cells (n = 3) transfected with Flag-mock or Ebp1. (D) Schematic image of the predicted Ebp1 binding site in the Bmp4 promoter region. (E) ChIP assay to measure Ebp1 binding in the promoter region in the Bmp4 gene (n = 3) using anti-RNA pol.II and Flag antibodies. (F) Luciferase activity of the pGL3-Bmp4 promoter in HT22 cells (n = 3) co-transfected with pGL3-Bmp4 WT or mutant along with a Flag-mock or Ebp1 plasmid. (G) ChIP assay with genomic DNA (gDNA) extracted from the mouse hippocampus (n = 3) at 12 months to measure DNMT1 binding in the promoter region of the Ascl1 gene. (H) gDNA digested with HpaII and MspI followed by amplification of Ascl1 CpG islands region (n = 3). (I) Luciferase activity of pGL3-Ascl1 promoter in HT22 cells (n = 3) co-transfected using pGL3-Ascl1 along with Flag-mock, Ebp1 FL, or Ebp1 ΔWH plasmid. Data indicate the mean ± SD of indicated numbers of independent experiments. **P < 0.01, ***P < 0.005, ****P < 0.001.
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