Enhanced De Novo Neurogenesis and Dopaminergic Neurogenesis in the Substantia Ni - 《stemcells》干细胞学杂志干细胞之家



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发表于 2009-3-5 00:06 |只看该作者 |倒序浏览 |打印

作者：Xiaoyang Shan, Liying Chi, Michael Bishop, Chun Luo, Lindsey Lien, Zheng Zhang, Rugao Liu作者单位：Department of Anatomy and Cell Biology, University of North Dakota School of Medicine, Grand Forks, North Dakota, USA + T2 Y$ T; B8 q, K3 C
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      【摘要】
   Research reports on de novo neurogenesis, particularly dopaminergic (DA) neurogenesis in the adult mammalian substantia nigra (SN), remain very controversial. For this reason, we used the nestin second intron enhancer-controlled LacZ reporter transgenic mouse model coupled with the 1-methyl-4-phyenyl-1,2,3,6-tetrahydropyridine (MPTP) lesion system to investigate whether there are neurogenesis and DA neurogenesis in the SN of the adult normal and Parkinson¡¯s disease (PD)-like mice. First, we demonstrated the presence of neural progenitor cells (NPCs), basal levels of neurogenesis, and DA neurogenesis in the normal adult mouse SN. Second, we showed that there is not only a significant increase in the number of NPCs but also a dramatic increase of neurogenesis from the NPCs in the SN and the midline region adjacent to the SN of the PD-like mice compared with that of normal controls. More importantly, we also demonstrated that there is an increase of DA neurogenesis in the SN of the MPTP-lesioned mice. Third, we showed that the increased DA neurogenesis in the MPTP-lesioned mice was derived from the NPCs and 5-bromodeoxyuridine-positive cells, suggesting that multiple stem cell lineages may contribute to the enhanced neurogenesis in the adult SN. Taken together, these results establish that there are basal levels, albeit low, and increased levels of de novo neurogenesis and DA neurogenesis in the SN of the adult normal and PD-like mice, respectively. The increased NPCs in the MPTP-lesioned mice further suggest that experimental approaches to promote de novo neurogenesis may provide an effective therapy for PD by functional replacement of degenerated DA neurons.
      【关键词】 Parkinsons disease -Methyl--phyenyl--tetrahydropyridine Dopaminergic cells Substantia nigra Neural progenitor cells De novo neurogenesis' A# g' l. t! d: t6 e( K
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It has been well established that neurogenesis occurs in the hippocampus . These results together demonstrate that there is neurogenesis in the normal adult CNS and elevated neurogenic responses in the degenerative CNS. The increased numbers of neural progenitor cells (NPCs) and enhanced neurogenesis in human patients with neurodegenerative complications, as well as in the animal models mimicking human degenerative diseases, suggest that measures of promoting de novo neurogenesis may have significant therapeutic potential.

Although substantial progress has been made in identifying and characterizing neuronal regeneration in the adult CNS, the research reports on neurogenesis, particularly dopaminergic (DA) neurogenesis in the adult mammalian substantia nigra (SN) remain very controversial. More recently, Zhao et al.  showed no evidence of DA regeneration and even no neurogenesis in the adult mammalian SN in either the normal or the chemical-induced PD-like rodent models using similar experimental procedures. To address the different observations, and more importantly, to identify whether there is de novo neurogenesis and DA neurogenesis in the adult SN, we applied the well-established nestin second intron enhancer-controlled LacZ reporter (pNes-LacZ) transgenic mouse model to identify NPCs and analyze their differentiation in the SN with neuron-specific and DA neuron-specific markers. We established that there are NPCs in the adult SN. More importantly, we showed that there are basal, albeit low, levels and increased levels of neurogenesis and DA neurogenesis in the SN of the adult normal and PD-like mice, respectively. Therefore, these results suggest that experimental approaches that facilitate de novo neurogenesis, particularly DA neurogenesis, may be potentially used for effective therapy of PD.

MATERIALS AND METHODS" B2 \4 @2 u8 q& O
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Transgenic Mice

Nestin is a marker for NPCs in the mammalian CNS  were used to identify NPCs and characterize neurogenesis and DA neurogenesis with specific neuronal markers. All experimental protocols were approved by the Institutional Animal Use and Care Committee at the University of North Dakota and are in agreement with the National Institutes of Health guideline for the care and use of laboratory animals.: x" ~- j9 T6 N

1-Methyl-4-phyenyl-1,2,3,6-tetrahydropyridine Lesion on Substantia Nigra in Adult Mice

Transgenic mice (pNes-LacZ) at 60¨C80 days of age were used for the vehicle control and 1-methyl-4-phyenyl-1,2,3,6-tetrahydropyridine (MPTP) lesion. Based on previous MPTP-induction mouse models .
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In Vivo 5-Bromodeoxyuridine Labeling% q( |( Q: T. \7 [) V" |" ?" G
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5-Bromodeoxyuridine (BrdU) (Sigma-Aldrich) at 50 mg/kg/day was i.p. administered for up to 15 days to adult pNes-LacZ transgenic mice . The mouse brain was dissected out 1 day after the last injection of BrdU and processed for BrdU detection and IHC analysis as described in the following section.
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LacZ Staining, Immunohistochemical Staining, Image Analysis, and Quantification) ~& `/ Q9 X* ~
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The SN region was used to identify NPCs and to analyze neurogenesis and DA neurogenesis. For LacZ staining, sections (12 µm) were incubated in 5-bromo-4-chloro-3-indolyl-ß-D-galactopyranoside (X-gal) solution for 16 hours at room temperature as previously described  at 1:300 dilution; anti-NeuN at 1:400 dilution; anti-BrdU at 1:400 dilution; all from Chemicon, Temecula, CA, http://www.chemicon.com) was then added to the blocking buffer, and the section was incubated at 4¡ãC overnight. The next day, sections were washed five times (5 minutes each) in 1x PBS (pH 7.5) containing 0.5% Triton X-100, followed by incubation with specific fluorescein-conjugated secondary antibody (all from Molecular Probes Inc., Eugene, OR, http://probes.invitrogen.com; 1:2,000 dilution) for 2 hours at room temperature. After extensive washes, sections were covered with anti-fade medium and sealed for fluorescent microscopic analysis. For negative control staining, sections were incubated without primary antibody.

All images were collected and analyzed with a Nikon fluorescent microscope 80I equipped with the Spot digital camera and Adobe Photoshop software. A confocal microscope (LSM510; Carl Zeiss, Jena, Germany, http://www.zeiss.com) was used to confirm the colocalization of double labeling.
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Quantification and Statistical Analysis
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Quantifications of LacZ-positive alone, LacZ- and NeuN-positive, LacZ- and TH-positive, and BrdU- and TH-positive cells in the SN were manually counted every 10th section between bregma ¨C2.70 and bregma ¨C3.80 of the mouse brain stereotaxic coordinates under a fluorescent microscope. This method of quantification for LacZ (NPCs) analysis eliminates the potential false positive effect that may be caused by the background. The number of cells from bilateral SN were added together and averaged for three mice. All the LacZ- and NeuN-positive, LacZ- and TH-positive, and BrdU- and TH-positive cells in the SN or the midline region adjacent to SN were confirmed with a Zeiss LSM510 confocal microscope. Statistical analysis of the MPTP-lesioned mice compared with that of vehicle controls was performed using the paired Student¡¯s t test. p 0 L9 `3 R6 H, G4 M0 o
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RESULTS- Y  Z' }! A7 }8 y" K+ u. m4 u; O4 r

There Are NPCs and Basal Levels of Neurogenesis in the Adult Mouse SN% A3 ^9 `; L' A# r; d

Previous reports on the neurogenesis and DA neurogenesis in the adult mammalian SN provided conflicting results , we did not find significant changes in the number of TH-positive cells in the SN of animals 50¨C180 days of age (data not shown). Therefore, we used mice 60¨C80 days of age for the studies of neurogenesis and DA neurogenesis in the adult mouse SN in the current report. With the pNes-LacZ transgenic mouse model, we demonstrated that there are NPCs in the adult mouse SN as identified by LacZ reporter staining (Fig. 1A, 1B), although the number of NPCs in the SN is much lower than that in the hippocampus (Fig. 1C, 1D) and olfactory bulb (data not shown). In addition, we also detected that there are basal levels of neurogenesis from the NPCs in the adult mouse SN, as measured by LacZ and NeuN double staining (Fig. 1A, 1B). Further analysis with confocal microscope confirmed that NeuN staining and LacZ staining are colocalized in the same cells (Fig. 1B, inset). However, we did not detect DA neurogenesis from the NPCs in the normal adult mouse SN (n = 3 normal control mice ranging from 60¨C80 days of age).4 B, N5 W; F9 w) i
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Figure 1. There are NPCs and basal levels of neurogenesis in the normal adult mouse SN. (A): Representative fluorescent microscopic images of the normal mouse SN stained with LacZ (blue), anti-NeuN (red), and anti-TH (green) antibodies to identify NPCs, neurons, and DA neurons, respectively. Notably, some NPCs were colocalized with NeuN but not TH (overlay). (B): Representative fluorescent microscopic images of NPCs colocalized with NeuN, confirmed with confocal microscopic analysis (inset). (C): Representative fluorescent microscopic images of the adult normal mouse hippocampus dentate gyrus stained with LacZ (blue) and anti-NeuN (green) antibody to identify NPCs and neurons, respectively. (D): Average number of NPCs in the normal adult mouse SN and HC (n = 4 mice). Abbreviations: HC, hippocampus; NPC, neural progenitor cell; SN, substantia nigra; TH, tyrosine hydroxylase.& {5 K4 M# w! L0 X
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MPTP Lesion Depletes the Number of DA Neurons and Increases Neurogenesis in the SN& \9 t; ]2 o5 c5 i8 I/ ]( y# E
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Since the basal levels of neurogenesis were low and there was no DA neurogenesis detected from the NPCs in the normal adult mouse SN, we then asked whether DA degeneration in PD can promote substantial neurogenic and/or DA neurogenic responses. To this end, we adopted the well-established subchronic MPTP lesion system to generate DA degeneration mimicking PD in the pNes-LacZ transgenic mice . MPTP lesion depleted the number of TH-positive DA neurons (Fig. 2A) and increased the number of NPCs in the SN compared with that of vehicle controls (Fig. 2A, 2B). More importantly, some of the NPCs in the SN differentiated into neuron-like cells that were positive for NeuN staining (Fig. 2C). Further confocal analysis confirmed that the LacZ staining and NeuN staining are colocalized in the same cells (Fig. 2C, inset), demonstrating an increased neurogenesis from the adult NPCs. The quantification of neuron-like NPCs in the SN of the MPTP-induced and vehicle control mice is shown in Figure 2D.3 o; T# ~6 o0 V
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Figure 2. MPTP lesion depletes TH-positive dopaminergic (DA) neurons and increases NPCs and neurogenesis in the adult mouse SN. (A): Representative fluorescent microscopic images of MPTP-lesioned mice demonstrating that MPTP depletes TH-positive DA neurons and increases the number of NPCs in the SN. (B): Quantification of NPCs in the SN of vehicle control mice (n = 3), MPTP10d (n = 3; *, p - D2 e8 ^. }* W) ~) ?# I

To test whether the increased number of NPCs in the SN is from proliferation in situ, we carried out BrdU labeling for up to 15 days of i.p. injection. The number of BrdU-positive cells in the SN (Fig. 3A, 3B) and midline vicinity to the SN (Fig. 3C, 3D) was increased in the MPTP-lesioned mice (Fig. 3B, 3D) compared with that of control mice (Fig. 3A, 3C). However, most of the NPCs did not colocalize with BrdU-positive cells in the SN (Fig. 3A, 3B), suggesting that the increased NPCs are not derived from the proliferation in situ. Thus, the increased NPCs in the SN after MPTP lesion may result from migration. On the other hand, the percentage of NPCs colocalized with BrdU in the midline vicinity region (adjacent to the SN) was increased (Fig. 3C, 3D). Further confocal analysis confirmed the colocalization of LacZ and BrdU (Fig. 3E, 3F).

Figure 3. 1-Methyl-4-phyenyl-1,2,3,6-tetrahydropyridine (MPTP) lesion increases BrdU-positive cells in the adult mouse substantia nigra (SN) and adjacent midline region to the SN. (A): Representative fluorescent microscopic image of the control mouse SN stained with LacZ (blue), anti-BrdU (red), and anti-tyrosine hydroxylase (TH) (green) antibodies. (B): Representative fluorescent microscopic image of the MPTP-lesioned mouse SN stained with LacZ (blue), anti-BrdU (red), and anti-TH (green) antibodies. Most of the neural progenitor cells (NPCs) in the SN do not colocalize with BrdU. (C): Representative fluorescent microscopic image of the control mouse midline region adjacent to the SN, stained with LacZ (blue), anti-BrdU (red), and anti-TH (green) antibodies. Some of the NPCs in the midline region colocalize with BrdU. (D): Representative fluorescent microscopic image of the MPTP-lesioned mouse midline region adjacent to the SN, stained with LacZ (blue), anti-BrdU (red), and anti-TH (green) antibodies. Some of the NPCs in midline region adjacent to the SN colocalize with BrdU. Notably, there are more NPCs and BrdU-positive cells detected in the midline region adjacent to the SN of the MPTP-lesioned mice than in that of controls. (E): Representative confocal microscopic images showing LacZ staining and anti-BrdU staining are colocalized in the same cells in the midline region adjacent to the SN of the control mice. (F): Representative confocal microscopic images showing LacZ staining and anti-BrdU staining are colocalized in the same cells in the midline region adjacent to the SN in the MPTP-lesioned mice. Abbreviations: BrdU, 5-bromodeoxyuridine; MPTP15d, MPTP-lesioned mice at 15 days.

In addition to the increased NPCs and neurogenesis in the SN (Fig. 2), we also observed a dramatic increase in the number of NPCs in the midline regions adjacent to the TH-positive DA neurons in the SN of the MPTP-lesioned mice (Fig. 4B), in comparison with that of vehicle controls (Fig. 4A). More significantly, some of the NPCs in the controls and MPTP-lesioned mice were positive for NeuN staining (Fig. 4A¨C4C). Further confocal analysis showed that NeuN staining and LacZ staining are in the same cells (Fig. 4A, 4B, insets). The quantification of NPCs and NeuN-positive NPCs in the midline region adjacent to the SN was shown in Fig. 4C. These NPCs were apparently in the process of migrating toward the SN, based on the analysis of MPTP-induced time dependent lesion (data not shown).* C- h& J5 [  S+ h+ }( X/ ^
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Figure 4. 1-Methyl-4-phyenyl-1,2,3,6-tetrahydropyridine (MPTP) lesion increases neurogenesis in the adult mouse midline region adjacent to the substantia nigra (SN). (A): Representative fluorescent microscopic images of the control mouse midline region adjacent to the SN stained with LacZ (blue) or anti-NeuN (red) antibody, showing that some of the LacZ-positive cells are NeuN-positive. Confocal analysis confirmed the colocalization of LacZ and NeuN (inset). (B): Representative fluorescent microscopic images of the MPTP-lesioned mouse midline region adjacent to the SN stained with LacZ (blue) or anti-NeuN (red) antibody, showing that some of the LacZ-positive cells are NeuN-positive. Confocal analysis confirmed the colocalization of LacZ and NeuN (inset). (C): Quantification of NPCs and neurogenesis from NPCs in the midline region adjacent to the SN in the vehicle control and MPTP-lesioned mice (Control: n = 3; MPTP10d: n = 3; MPTP15d: n = 3; *, p
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MPTP Lesion Promotes DA Neurogenesis from the NPCs and the BrdU-Positive Cells in the Adult Mouse SN# p* j  ~7 x3 R1 f  w' z- Y+ P
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The increased neurogenesis in the SN and the midline region adjacent to the SN prompted us to analyze whether there is enhanced DA neurogenesis as a result of MPTP lesion. LacZ staining and TH labeling demonstrated that some NPCs in the SN are TH-positive (Fig. 5A). Further analysis with confocal microscope confirmed the LacZ staining and TH labeling are in the same cell (Fig. 5A, insets), indicating that there is DA neurogenesis in the SN of MPTP-lesioned mice. The quantification of DA neurogenesis from NPCs in the adult mouse SN (from bregma ¨C2.70 to bregma ¨C3.80 of the mouse brain stereotaxic coordinates) is shown in Fig. 5B (n = 4 for control mice; n = 3 for MPTP10d mice; n = 3 MPTP15d mice).4 P+ @* V; F# P1 k# l6 n

Figure 5. 1-Methyl-4-phyenyl-1,2,3,6-tetrahydropyridine (MPTP) lesion increases dopaminergic (DA) neurogenesis in the adult mouse SN. (A): Representative fluorescent microscopic images of the vehicle control mouse SN stained with LacZ (blue) and anti-TH (green) antibody to identify DA neurogenesis from NPCs. Confocal analysis confirmed that the LacZ staining and TH staining were colocalized in the same cells (insets). (B): Quantification of DA neurogenesis from NPCs in the SN of vehicle control and MPTP-lesioned mice (Control: n = 3; MPTP10d: n = 3; MPTP15d: n = 3; *, p

Similarly, we also demonstrated that there is an increase of DA neurogenesis from some of the BrdU-positive cells in the SN of MPTP-lesioned mice (Fig. 5C, 5D). Double (BrdU and TH) labeling and quantitative analyses showed there is a significant increase of the DA neurogenesis from BrdU-positive cells in the MPTP-lesioned mice compared with that of vehicle controls (Fig. 5E) (n = 4 for control mice; n = 3 MPTP15d mice). These data together demonstrate that MPTP-mediated DA degeneration promotes DA neurogenesis in the SN.% T  w! X% q* \6 _" S8 i8 Y7 {
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DISCUSSION4 h% J2 I  [6 M/ T! l

Although much evidence has demonstrated that neurogenesis is present in the adult mammalian CNS, the status of neurogenesis, particularly DA neurogenesis in the SN, has not been unambiguously defined. Most of the previous studies relied on the colocalization of BrdU labeling and a specific neuronal marker(s) and/or a DA neuron marker(s) to define neurogenesis and/or DA neurogenesis in the adult SN ; and (b) by coupling LacZ staining with BrdU labeling and specific neuron identification, we can define the proliferation and differentiation status of the BrdU-positive cells and NPCs in the SN. The present study using the pNes-LacZ transgenic mice demonstrates three major findings: (a) There are basal levels of neurogenesis and DA neurogenesis detected in the normal adult mouse SN, (b) MPTP lesion depleting DA neurons promotes neurogenesis and DA neurogenesis in the adult mouse SN, and (c) MPTP lesion-induced DA neurogenesis may be derived from multiple stem lineages, including the NPCs and BrdU-labeled proliferative cells. Taken together, this study provides compelling evidence supporting the presence of the basal levels of neurogenesis in the normal adult mouse SN and enhanced DA neurogenesis in the MPTP-lesioned mice mimicking PD.7 S. S( }  z( J8 F
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Our findings with the pNes-LacZ transgenic mice using both BrdU labeling and NPC identification approaches establish that there is de novo neurogenesis and DA neurogenesis in the adult SN. However, the rate of basal levels of neurogenesis and DA neurogenesis is low in the normal adult mouse SN as compared with that of hippocampus and olfactory bulb (Figs. 1, 2) . For the IHC staining, we used the sections at 12-µm thickness, which allows the antibody to thoroughly penetrate to the cellular and subcellular structures. For double labeling and detection, all images were initially analyzed with fluorescent microscope and subsequently confirmed with confocal microscope. More importantly, we analyzed the neurogenesis and DA neurogenesis from NPCs and BrdU-positive cells. With these identification approaches, we demonstrated that there are basal levels of neurogenesis in the adult SN (Figs. 1A, 1B, 1D, 2D). In addition, we showed that there is DA neurogenesis from the BrdU-positive cells (Fig. 5), although we did not detect DA neurogenesis from the NPCs in the normal adult SN (Figs. 1A, 5B).1 _: x) v) o7 I1 H% m

After MPTP lesion, there was an increase of NPCs (Fig. 2) and BrdU-positive cells (Fig. 3) in the SN. More significantly, there was enhanced neurogenesis and DA neurogenesis detected from NPCs and BrdU-positive cells (Fig. 5). The reports from Zhao et al.  suggest a possibility of neurogenesis in SN of Parkinsonian brain. The large number of NPCs and BrdU-positive cells and low DA neurogenesis rate in the MPTP-lesioned SN further provide a rationale for therapy of DA degeneration in PD by stimulation of de novo neurogenesis from both NPCs and BrdU-positive cells.3 m2 m7 T" M0 }; {- z* j/ E0 G) k
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One important but not unambiguously resolved issue in previous and current studies is where the increased NPCs come from in the MPTP-lesioned mice. Based on the distribution pattern, colocalization of LacZ staining, and BrdU labeling, we think that the increased NPCs in the SN are derived from the subventricular zone. Although most of the NPCs distributed in the SN do not label with BrdU, the LacZ-positive NPCs in the ventricular systems, particularly in the ependymal layer, were stained with BrdU, indicating that these NPCs are proliferative (data not shown). Since there are NPCs in the SN and these NPCs were not proliferative in situ, we reasoned that the increased NPCs in the MPTP-lesioned mouse SN are putatively derived from the cerebroventricular system. However, extensive analyses are required to determine and to define the migratory pathways of NPCs from subventricular zone to the SN in response to DA neuron degeneration.- l7 k: \: B  G  f/ z* w: P

In summary, using the pNes-LacZ transgenic mouse model and MPTP lesion system mimicking PD, we demonstrated that degeneration of DA neurons increases the number of NPCs and promotes neurogenesis and DA neurogenesis in the adult SN compared with that of normal controls. The newly generated DA neurons after MPTP lesion apparently result from different stem cell lineages. The increased NPCs, neurogenesis, and DA neurogenesis in the PD-like mice suggest that experimental approaches that enhance de novo neurogenesis may contribute significantly to the effective therapy of PD.

ACKNOWLEDGMENTS
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This study was supported in part by National Institutes of Health grants (NS45829, HL75034, and AG23923) and by a Muscular Dystrophy Association grant.

DISCLOSURES5 c7 b( X$ g; R7 P7 c! r! f# b
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The authors indicate no potential conflicts of interest.1 V+ P2 }6 O  X
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