Zbtb20 Regulates Developmental Neurogenesis in the Olfactory Bulb and Gliogenesis After Adult Brain Injury
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The transcription factor (TF) Zbtb20 is important for the hippocampal specification and the regulation of neurogenesis of neocortical projection neurons. Herein, we show a critical involvement of the TF Zbtb20 in the neurogenesis of both projection neurons and interneurons of the olfactory bulb during embryonic stages. Our data indicate that the lack of Zbtb20 significantly diminishes the generation of a set of early-born Tbr2+ neurons during embryogenesis. Furthermore, we provide evidence that Zbtb20 regulates the transition between neurogenesis to gliogenesis in cortical radial glial progenitor cells at the perinatal (E18.5) stage. In the adult mammalian brain, Zbtb20 is expressed by GFAP+ neural progenitor cells (NPCs) located in the forebrain neurogenic niche, i.e., the subventricular zone (SVZ) of the lateral ventricles. Upon induction of cerebral ischemia, we found that Zbtb20 expression is upregulated in astrocytic-like cells, whereas diminishing the expression levels of Zbtb20 significantly reduces the ischemia-induced astrocytic reaction as observed in heterozygous Zbtb20 loss-of-function mice. Altogether, these results highlight the important role of the TF Zbtb20 as a temporal regulator of neurogenesis or gliogenesis, depending on the developmental context.
KeywordsZbtb20 Olfactory bulb Post-natal progenitor cell Astrocyte Stroke
The neocortex of mammals contains numerous neuronal and glial subtypes, predominantly generated during the embryonic (neurons) and perinatal (glia) developmental stages. Both neurons and glia are produced by radial glial stem cells (RGSCs), which reside in the embryonic ventricular zone (VZ), in a specific sequence. Neurogenesis, mostly accomplished during embryogenesis, precedes gliogenesis that occurs at perinatal stages and continues post-natally . The neurogenesis of neocortical layer neurons follows a specific temporal sequence as deep (lower) layer neurons are produced before neuronal subtypes located in superficial (upper) layers [2, 3, 4]. The regulation of the sequential generation of layer specific neuronal subsets is not well understood, and to date, only a few genes have been implicated in this process, including chicken ovalbumin upstream promoter-transcription factor (COUP-TF)1 [5, 6], FoxG1 , Gli3 , Brn2 , zinc finger, and BTB domain-containing 20 (Zbtb20) . The precise mechanisms of the transition between neurogenesis and gliogenesis also remain obscure . Some of the known regulators directly induce gliogenesis from the RGSCs. These include transcription factors (TFs), such as nuclear factor IA (NFIA), high-mobility group (HMG) box family member Sox9, Zbtb20 [12, 13, 14], as well as Notch signaling  and microRNA(miR)-153 . Other factors activate gliogenesis by endowing the RGSCs with a gliogenic competence, including COUP-TF1/2  and miR-17/106 .
Similar to the neocortex, the olfactory bulb (OB) contains two types of neurons: glutamatergic projection neurons (mitral and tufted cells) and GABAergic interneurons, mostly situated in the granular and glomerular layers (GLs) . In addition, a small population of glutamatergic interneurons exists. Similar to neocortical neurogenesis, the generation of OB neuronal subtypes starts at stage E11 by forebrain VZ RGSCs which first produce the glutamatergic projection neurons in an inside-first-outside-last schedule (mitral cells followed by tufted cells) [19, 20]. Later in development as well as post-natally, a heterogeneous set of glutamatergic periglomerular neurons, marked by the expression of T-Box TFs Tbr1 and Tbr2, are produced . Gradually, the production of glutamatergic neurons slows down, which parallels the arrival into the OB of GABAergic interneurons that are generated mostly from the embryonic dorsal lateral ganglionic eminence (dLGE) . They migrate along the rostral migratory stream (RMS) and incorporate into the OB [23, 24].
The TF Zbtb20 was previously reported to play a critical role in hippocampal neurogenesis and subfield specification [25, 26, 27, 28, 29]. Recently, we have revealed an involvement of Zbtb20 in the timely generation of neocortical glutamatergic neuronal subsets . Here, we show that in the OB, Zbtb20 regulates neurogenesis not only of glutamatergic projection neurons but also of the glomerular GABAergic interneurons (INs) and astrocytes. The analysis revealed that at post-natal stages, a high Zbtb20 expression level defines a subpopulation of GFAP+ precursor cells including neural stem cells (NSCs), which respond to ischemic brain injury. Notably, decreased levels of Zbtb20 in transgenic mice lead to a reduced post-stroke gliogenic scar, suggesting a requirement of Zbtb20 for gliogenesis after pathological conditions, such as ischemic brain injury.
Materials and Methods
Animals were handled in accordance with the German Animal Protection Law and approved by local authorities. All surgical procedures were performed under isoflurane/N2O anesthesia, and all efforts were made to minimize suffering. The Zbtb20 gene targeting and the generation of the transgenic mice have been previously described . The Zbtb20 knock out (KO) mice lack the functionally important BTB/POZ domain of the protein as well as the first of five zinc fingers, which were replaced by a lacZ-neomycin cassette. Therefore, homozygous mutants will be referred to as Zbtb20 lacZ/lacZ mice within this study. The specificity of the deletion and the complete loss of Zbtb20 protein have been confirmed as described . The transgenic mice which express the Cre recombinase under the control of the hGFAP promoter  and the Rosa-lacZ reporter strain which carries β-galactosidase (β-gal) as an endogenous marker  were previously described.
Cerebral ischemia was induced using middle cerebral artery occlusion (MCAO) as previously described . Briefly, animals were anesthetized (0.8–1.5% isoflurane, 30% O2, remainder N2O), and rectal temperature was maintained at 36.5–37.0 °C, employing a feedback-controlled heating system under a continuous control of blood flow changes by means of a laser Doppler flow (LDF) system (Perimed, Sweden). Occlusion of the middle cerebral artery was achieved using a 7–0 silicon coated nylon monofilament (180-μm tip diameter; Doccol, USA), which was withdrawn after 45 min to induce transient cerebral ischemia. LDF recordings continued for an additional 15 min to monitor appropriate reperfusion.
Histological Processing and Immunohistochemistry
Isolated embryos or brains at defined stages were washed in cold phosphate-buffered saline (PBS) and fixed in 4% paraformaldehyde (PFA) overnight at 4 °C. Tissues were rinsed in PBS and processed for standard cryoembedding. Cryosections (16-μm thick) were washed and blocked for 1 h in blocking solution containing a normal serum. Primary antibodies were incubated overnight at 4 °C in the blocking solution. After washing, the sections were incubated with species-specific secondary antibodies from the Alexa series (Invitrogen) in blocking solution for 2 h at room temperature (RT), washed again, and mounted with Vectashield mounting-medium (Vector Labs) containing DAPI. We used the following primary antibodies/dilutions: mouse anti-β-galactosidase (1:200; Promega, Madison, WI), rat anti-BrdU (1:200; Abcam, Cambridge, UK), rabbit anti-calretinin (1:500, Swant, Bellinzona, Switzerland), goat anti-calretinin (1:300, Millipore/Merck Chemicals GmbH, Darmstadt, Germany) mouse anti-CoupTF1 (1:1000; Perseus Proteomics, Tokyo, Japan), rabbit anti-Cux1 (1:250; Santa Cruz, CA, USA), rabbit anti-doublecortin (DCX; 1:400; Abcam), guinea pig anti-doublecortin (1:300; Millipore), chicken anti-GFAP (1:2000; Abcam), rabbit anti-GFAP (1:200; DAKO, Carpinteria, CA, USA), rabbit anti-NG2 (1:300; Millipore), rabbit anti-nNOS (1:5000; Alexis Chemicals; San Diego, CA, USA), mouse anti-TH (1:300; Millipore), rabbit anti-calretinin (1:1000, Swant), rabbit anti-calbindin (1:1000, Swant), and rabbit anti-Zbtb20 (1:100, Sigma-Aldrich, Taufkirchen, Germany). The anti-BrdU antibodies were visualized after pre-treatment of tissues in 2-N HCl at 37 °C for 30 min. The anti-Zbtb20 antibody was used after an antigen retrieval by heating in a microwave (800 W, three times, 5 min each) in a citrate buffer (pH 6.0).
In Situ Hybridization
Whole heads from E12.5 or whole brains from E18.5 or P4 mice were dissected in ice-cold DEPC-treated PBS, fixed in 4% PFA/PBS for 3 h at 4 °C, washed in PBS, and incubated in 25% sucrose overnight at 4 °C. Specimens were sectioned at 16 μm after embedding and freezing in OCT cryomatrix (Leica Microsystems Nussloch GmbH, Wetzlar, Germany). Non-radioactive in situ hybridization was done as described before.
Image Analysis and Quantification
Images were captured with an Olympus BX60 microscope, a Leica DM6000 epifluorescent system, or a laser confocal microscope (Leica SP5). For cell counts in sections from wild type (WT) and homozygous brains, we blindly counted the positive cells within equally sized frames on coded cross sections of somatosensory cortex in WT and mutant mice (n ≥ 3 per genotype). Laser confocal microscopy was used to verify co-localization of multiple fluorescent signals. We performed Z sectioning at 0.5–1-μm intervals, and optical stacks of at least 10 images were used for analysis, using the Leica Advanced Fluorescence software version 2.3.6. All images were processed with Adobe Photoshop (Version CS2) by overlaying the pictures, adjusting brightness, contrast, and size.
Statistical evaluation was performed by Student’s T test or one-way ANOVA followed by Tukey-Kramer’s post hoc analysis. Statistical significance between control and experimental condition was considered if p < 0.05. Data are presented as means ± s.e.m.
Neuronal Defects in OB of Zbtb20LacZ/LacZ Mice
Expression of Zbtb20 Marks Progenitors in the Post-Natal SVZ Stem Cell Niche
Zbtb20 is expressed in the post-natal SVZ of the forebrain lateral ventricle , a site of continuous generation of progenitor cells migrating to the OB via the RMS. To gain a deeper insight into the expression of Zbtb20 in the post-natal SVZ neurogenic niche, we performed a detailed analysis of Zbtb20 expression in its cellular components stem-like “B cells,” transit amplifying progenitors (“C cells”), and neuroblasts (“A cells”) . Based on the expression level of Zbtb20 by IHC, the Zbtb20+ cells in the SVZ can be visually classified as Zbtb20+ cells with a high (Zbtb20hi) or a low (Zbtb20lo) level of expression (Fig. 5A1, B1, C1; arrows and arrowheads, respectively). We calculated that nearly 60% (73 out of 124) of the Zbtb20+ cells were Zbtb20hi cells, and approximately 40% (51 out of 124 Zbtb20+ cells) were Zbtb20lo cells. Co-localization with GFAP showed that 2/3 (94 out of 142) of the Zbtb20hi cells co-expressed GFAP (Fig. 5A2; arrows), whereas almost none of the Zbtb20lo cells did so (< 1%; Fig. 5A2; arrowheads). Co-staining of Zbtb20 with Ki67, which predominantly stains the C cells, showed that 1/3 (28 out of 82) of the Zbtb20lo cells co-labeled with Ki67 (Fig. 5B1–B2; arrowheads), while only 2% (2 of 92) of the Zbtb20hi cells did so (Fig. 5B1–B2; arrows). Similar results were obtained using Ascl1, an alternative C cell marker (data not shown). Similar to Ki67, double staining of Zbtb20 with DCX, a marker of “A cells” (neuroblasts), resulted in a high percentage of co-expression in the Zbtb20lo cells (93%, 110 of 118 Zbtb20lo cells), while virtually none of the Zbtb20hi cells co-expressed DCX (Fig. 5C1–C2; arrowheads and arrows, respectively). Altogether, these results suggest that the expression level of Zbtb20 is high in the GFAP+ cells, part of which act as NSCs in the adult brain, while its expression gradually decreases in the transit amplifying “C” cells and in the “A” cells (neuroblasts).
Because of the early post-natal mortality of Zbtb20 lacZ/lacZ mice, we could not investigate the effect of Zbtb20 LOF on adult neurogenesis. The performed analysis of the early post-natal (P4) SVZ/RMS revealed in the mutant a greatly thickened RMS with a strongly reduced GFAP expression (Fig. 6A1–B2, dotted lines) and an accumulation of GFAP+ cells in the SVZ (Fig. 6A1–B2, asterisks). The thickening of RMS was still visible at P12 as depicted by DCX immunostaining (Fig. 6C1–C2, arrowheads), which also revealed clusters of DCX+ cells in the mutant subcortical WM adjacent to RMS (Fig. 6C2, arrow). Furthermore, we found a decreased immunoreactivity for the oligodendrocyte progenitor marker NG2 in the subcerebral white matter adjacent to RMS (Fig. 6D1–D2) and in the Olig2+ cells in the corpus callosum (WT: 30 ± 2 cells/frame, Zbtb20 KO: 20 ± 2 cells/frame 100 × 100 μm). Together, these results indicate a reduced gliogenesis in Zbtb20 lacZ/lacZ mice soon after the switch between neurogenesis and gliogenesis, suggesting an involvement of Zbtb20 in this process.
TF Zbtb20 Is Involved in Post-Ischemic Gliogenesis
Thus far, we have established that Zbtb20 is expressed by post-natal SVZ progenitors including the NSC fraction and that its levels affect the normal developmental genesis of glial populations, in particular astrocytes. The astrocyte response to injury, known as reactive gliosis, is highly prevalent after brain damage but is still poorly understood. Given the potential of Zbtb20 to affect astrocytic levels under normal conditions, we addressed its role under conditions of injury using an experimental stroke model . The application of this model inflicts damage on the ipsilateral striatum and cortex of adult mice. After stroke in WT mice, we found a significant increase in the number of Zbtb20+ cells along the ipsilateral SVZ as compared to the contralateral SVZ (Fig. 8A1–A2; insets). Statistical analysis confirmed the significance of this upregulation in the dorsal, lateral, and ventral SVZ (Fig. 8D). Notably, there was a marked increase of the Zbtb20+ cells also in the infarct area (Fig. 8A2; dotted lines) and the ipsilateral pyriform cortex (Fig. 8A2). To study cell proliferation after stroke, we continuously injected BrdU in the operated mice for 10 days starting at day 8 after stroke and sacrificed the animals on day 28 after stroke. We detected a prominent increase of BrdU+ cells in the ipsilateral hemisphere (Fig. 8B1–B2), which paralleled the post-ischemic increase of Zbtb20+ cells in the SVZ (Fig. 8B2; arrow) and the infarct area (Fig. 8B2; dotted lines).
Unlike TFs such as Sp8  and Pax6 , which are selectively involved in the neurogenesis of specific OB neuronal populations, we here show that Zbtb20 LOF affects nearly all OB neuronal types including glutamatergic and GABAergic neurons. The present report is the first to implicate the TF Zbtb20 in OB neurogenesis. Thus, Zbtb20 LOF leads to derangements not only of glutamatergic [10, 25, 26, 28, 29] but also of GABAergic neurons in the mammalian telencephalon, including the OB.
The enhancement of early-born glutamatergic OB neuronal types in Zbtb20 KO mice is in accordance with the increase of early born deep layer neocortical neurons in this mutant . The derangement of the interneuronal populations occurs largely prenatally and is supported by the following evidence: (i) expression of Zbtb20 in developing dorsal LGE and septum, the germinative zones of which produce OB INs (42,40); (ii) BrdU birthdating analysis showing deficits of generation of INs produced at all tested embryonic stages; and (iii) lack of co-expression between Zbtb20 and OB neuronal markers (with the exception of a few CR+ cells) at post-natal stages. Prenatally, we did not detect changes in the expression of TFs Sp8 (CR+ neurons; ), Gsx2 (LGE and septum-derived interneurons; ), and Pax6 (TH+ interneurons; ) in Zbtb20 LOF, while the expression of TFs ER81 and Meis2  was diminished. The molecular mechanisms of embryonically induced deficits in generation of interneurons of OB in Zbtb20 LOF require further investigation.
In addition to neuronal deficits, we found that the lack of Zbtb20 also leads to diminishing of the glial cells in the OB, which is in accordance with the data of Nagao et al. . Decrease was also observed in cortical and callosal astrocytes but not in L1 astrocytes suggesting that Zbtb20 differentially affects astrocyte populations in developing brain. The mechanisms by which Zbtb20 modulates astrocyte levels are possibly via the regulation of the onset of the cortical gliogenic program. At gliogenesis stages, Zbtb20 inhibits late-born neuronal fate [14, 27] allowing for activation of a gliogenic program in RGCs. We herein show that in a lack of Zbtb20, the onset of the gliogenic program is delayed and E18.5-born progenitors intensively generate Cux1+ neurons at the expense of glia, leading to an enhanced presence of DCX+ neurons and decreased GFAP+ glia in early perinatal Zbtb20 LOF telencephalon.
Zbtb20 Expression Identifies a Subset of Post-Natal SVZ Stem Cells Responding to Injury
After midgestation, a subpopulation of RGSCs progressively slows down their cell cycle, becomes quiescent, and contributes to the pool of adult SVZ NSCs [43, 44]. These cells are marked by their strong expression of the astrocyte marker glial fibrillary acidic protein (GFAP)  and exert a capacity to generate neurons for cell replacement in the OB of adult mammals . In addition to neurogenesis, the SVZ stem cells are capable of producing oligodendrocytes  or astrocytes  in the mouse corpus callosum but not in the striatum or the cortex under normal conditions. However, cerebral injury such as stroke is capable of redirecting neuroblasts from their migration to the OB into the affected striatum and cortex [48, 49] or activate a gliogenic program in SVZ progenitors resulting in reactive oligodendrogliogenesis  or astrogenesis [51, 52].
Our results provide first data that TF Zbtb20 is expressed by adult SVZ stem cells. The program of adult neurogenesis in the SVZ involves several consecutive steps including division of stem cell-like GFAP+ astrocytes (B cells) in the forebrain SVZ stem niche, followed by generation of transit amplifying (Ki67+/Ascl1+) (C cells), and finally, generation of doublecortin DCX+/βIII-tubulin+ neuroblasts (“A cells”) that migrate to OB and regenerate interneurons throughout the life . The stem cell population can be identified by its high expression of GFAP, the retention of BrdU label after long infusion period and by its adherence within the hGFAP-Cre lineage . Our analysis revealed that TF Zbtb20, known to predominantly act as a repressor , is expressed in the post-natal SVZ niche, showing gradual decrease during the differentiation (B → C → A) of the stem cells. This gradual decrease of Zbtb20 expression in maturating SVZ cells suggests that a successful neuronal differentiation in the post-natal brain might require a decline in Zbtb20 repressive activity. Indeed, we found that DCX+ neuroblasts were enhanced in the absence of Zbtb20 as seen in early post-natal Zbtb20 lacZ/lacZ mice, while GFAP+ and the gliogenic NG2+ progenitors were reduced. This is consistent with the finding of Nagao et al.  and supports their conclusion that in the post-natal brain, Zbtb20 is expressed in a subpopulation of bipotent (astrocytic and oligodendroglial) progenitors.
To obtain a deeper insight into whether the Zbtb20 expression is responsive to a brain injury, we applied a brain stroke model to adult hGFAP-Cre reporter which allows a transgenic lineage tracing of SVZ NSCs . Stroke activates SVZ progenitors to produce both neuroblasts and glial cells, but only the glial cell survives in longer periods after the insult [49, 55]. Our analysis indicated a massive enhancement of de novo generated Zbtb20+ cells and an increase of Zbtb20+/GFAP+ cells traced to the β-gal+ lineage along the dorsal, lateral, and ventral SVZ in the ipsilateral side of the stroke. Similarly, the ipsilateral pyriform cortex showed a massive accumulation of Zbtb20+ and hGFAP-Cre lineage cells. Recent data indicate that at this location, some NG2+ progenitor cells reside [56, 57] that are within the hGFAP-Cre lineage  and can be activated by cerebral ischemia .
To shed light onto the possible functional relevance of the post-natal Zbtb20 expression after a stroke, we applied the MCAO model in heterozygous Zbtb20 +/lacZ mice, which survive until adulthood. Notably, the heterozygous Zbtb20 +/lacZ mutants were characterized by a smaller GFAP+ scar in the injured striatum adjacent to SVZ. These findings suggest an involvement of Zbtb20 in the regulation of the gliogenic response after brain injury. Experiments allowing a conditional elimination of the TF Zbtb20 in the brain SVZ niche are required to define more precisely the function of Zbtb20 in respect to the regenerative capacity of the adult brain. Interestingly, a recent genome-wide association study identified the ZBTB20 gene as a risk locus for ischemic stroke in humans , thus warranting further investigation of the role of the TF in cerebral ischemia.
A.B.T. and A.S. designed research. A.B.T., T.R.D., and J.H. performed research. T.R.D., A.S., M.B., and A.B.T. analyzed data. T.R.D., A.S., and A.B.T. wrote the manuscript.
Compliance with Ethical Standards
The authors declare that they have no competing interests.
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