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Previous Article | Next Article
The Journal of Neuroscience, November 1, 2002, 22(21):9387-9398
Insulin and Fibroblast Growth Factor 2 Activate a Neurogenic Program in Müller Glia of the Chicken Retina
Andy J. Fischer, Christopher Roger McGuire, Blair Dorian Dierks, and Thomas A. Reh Department of Biological Structure, University of Washington, Seattle, Washington 98195
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
We have reported previously that neurotoxic damage to the chicken retina causes Müller glia to dedifferentiate, proliferate, express transcription factors common to retinal progenitors, and generate new neurons and glia, whereas the majority of newly produced cells remain undifferentiated (Fischer and Reh, 2001
). Because damaged retinal cells have been shown to produce increased levels of insulin-related factors and FGFs, in the current study we tested whether intraocular injections of growth factors stimulate Müller glia to proliferate and produce new neurons. We injected growth factors and bromodeoxyuridine into the vitreous chamber of the eyes of chickens and assayed for changes in glial phenotype and proliferation within the retina. Although insulin or FGF2 alone had no effect, the combination of insulin and FGF2 caused Müller glia to coexpress transcription factors common to retinal progenitors (Pax6 and Chx10) and initiated a wave of proliferation in Müller cells that began at the retinal margin and spread into peripheral regions of the retina. Most of the newly formed cells remain undifferentiated, expressing Pax6 and Chx10, whereas some differentiate into Müller glia, and a few differentiate into neurons that express the neuronal markers Hu or calretinin. There was no evidence of retinal damage in eyes treated with insulin and FGF2. We conclude that the combination of insulin and FGF2 stimulated Müller glia to dedifferentiate, proliferate, and generate new neurons. These findings imply that exogenous growth factors might be used to stimulate endogenous glial cells to regenerate neurons in the CNS.
Key words: retina; insulin; FGF2; chick; Müller glia; regeneration; stem cell; progenitor
INTRODUCTION
The potential for neural regeneration in the adult CNS of warm-blooded vertebrates has increased in likelihood with the discovery of neural stem cells. Several studies have demonstrated that particular types of neurons can be regenerated in the cortex of mice (Magavi et al., 2000
As noted above, recent evidence indicates that the retina of chickens has the ability to regenerate neurons. In response to neurotoxic damage, numerous Müller glia dedifferentiate, proliferate, express transcription factors (Cash1, Pax6, and Chx10) common to retinal progenitors, and produce new neurons (Fischer and Reh, 2001a
Like FGFs, insulin and insulin-like growth factors (IGFs) may be involved in the Müller glial response to injury. During embryonic retinal development, IGF-I is transiently expressed by Müller glia and pigmented epithelial cells (Hansson et al., 1989
We found that intraocular injection of a combination of insulin and FGF2, but not insulin or FGF2 alone, had a variety of influences on postmitotic Müller glia, including: (1) suppression of glutamine synthetase (GS) expression, (2) re-entry into the cell cycle in the absence of retinal damage, (3) expression of Pax6 and Chx10, and (4) production of new glia and neurons.
METHODS AND MATERIALS
Animals. The use of animals in these experiments was in accordance with the guidelines established by the National Institutes of Health and the University of Washington. Newly hatched leghorn chickens (Gallus gallus domesticus) were obtained from H&N Highline International (Seattle, WA) and kept on a 16/8 hr light/dark cycle (lights on at 6:00 A.M.). Chicks were housed in clear Nalgene cages at ~25°C and received water and Purina chick starter ad libitum.
Injections. Chicks were anesthetized and injected as described previously (Fischer and Reh, 2000
Fixation and sectioning. Dissection, fixation, and sectioning were performed as described previously (Fischer et al., 1998
Immunocytochemistry. Standard immunocytochemical techniques were applied as described previously (Fischer et al., 1998
3 tubulin at 1:1000 (TUJ-1; Covance), mouse anti-RA4 (Dr. S. McLoon, University of Minnesota, Minneapolis, MN), mouse anti-neurofilament at 1:80 (recognizes the phosphorylated 200 kDa isoform of neurofilament; RT97; DSHB), rat anti-BrdU at 1:80 (Accurate Chemicals, Westbury, NY), and mouse anti-BrdU at 1:80 (G3B4; DSHB). Secondary antibodies included goat anti-rabbit-Alexa568, goat anti-mouse-Alexa568, goat anti-mouse-Alexa488, and goat anti-rat-Alexa488 (Molecular Probes, Eugene, OR) diluted to 1:500 in PBS (0.05 M phosphate buffer and 145 mM NaCl, pH 7.4) plus 0.3% Triton X-100.
Labeling for fragmented DNA. 3' nick-end labeling was performed as described previously (Fischer et al., 1998
Measurements, cell counts, and statistical analyses. Errors were calculated as the SD of each sample that was composed of at least five individuals per group. To compare data from treated and control eyes, statistical significance was assessed by using a two-tailed Student's t test or ANOVA and post hoc Student's t test. All measurements were made from digital micrographs of the retinal margin, whereas all cell counts were made under the microscope on at least four different sections per individual.
RESULTS
Insulin and FGF2 induce proliferation and accumulation of progenitor-like cells in the retina
To deliver growth factors to the retina, we made one to three consecutive daily intraocular injections starting at P7 of insulin alone (2 µg per dose), FGF2 alone (100 ng per dose), or insulin and FGF2 together. We assayed whether exogenous growth factors stimulate proliferation within the retina by injecting BrdU with the growth factors into the eye and probing for incorporation of BrdU and expression of proliferating cell nuclear antigen (PCNA) by using indirect immunofluorescence on retinal sections. In retinas treated with insulin alone (Fig. 1a) or two consecutive daily injections of insulin and FGF2 (data not shown), we found BrdU/PCNA-labeled cells only at the peripheral edge of the retina in the progenitor zone at the retinal margin. These findings are consistent with previous reports (Fischer and Reh, 2000
600 µm) than those observed at 6 hr after the final injection (Fig. 1c). Forty-eight hours after the last injection of insulin and FGF2, the percentage of BrdU/PCNA-labeled cells within the retinal section was reduced (10.1 ± 8.3%) from that observed at 6 hr after the final injection of growth factors. This percentage was region specific; within 500 µm of the retinal margin, 38.1 ± 7.6% of the PCNA-expressing cells were labeled for BrdU (Fig. 1g), whereas within >600 µm from the retinal margin, none of the PCNA-expressing cells were labeled for BrdU (Fig. 1f). Ten days after the final injection of insulin and FGF2, numerous BrdU-labeled cells remained in the retina, in a pattern similar to that observed at 48 hr after the final injection of growth factors. BrdU-labeled cells were found only in peripheral regions of the retina, within 1 mm of the retinal margin, whereas PCNA-labeled cells were found in
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Figure 1. Exogenous insulin and FGF2 stimulate the proliferation of cells within peripheral regions of the retina. Vertical sections of the retina were labeled with antibodies to PCNA (in red) and BrdU (in green). Cells double labeled for PCNA and BrdU appear yellow, because all BrdU-labeled cells express PCNA. a-c, Montage images of retinas from eyes that received three consecutive daily injections of BrdU with insulin (a, d) or insulin with FGF2 (b, c, e-g). Injections were made from P7 through P9, and eyes were harvested 6 hr (b, e), 24 hr (a, d), or 48 hr (c, f, g) after the final injection. d-g, Enlarged images of the areas boxed out in green in a-c. Arrows, Retinal margin. Scale bars: b (for a, b), c (for d-f), 200 µm; g, 50 µm. GCL, Ganglion cell layer.
To test whether insulin and FGF2 induce a wave of proliferating cells, we made three consecutive daily injections of these growth factors without BrdU and provided BrdU at different times after the final injection of growth factors. In retinas that were treated with BrdU 6 hr after the final injection of insulin and FGF2, we observed many BrdU/PCNA-labeled cells within the peripheral retina, within 500 µm of the retinal margin, but not including substantial numbers of cells within the progenitor zone (Fig. 2a,e). We also found many cells labeled for PCNA alone, extending ~700 µm into the retina (Fig. 2a,e). In eyes that were injected with BrdU 12 hr after the final injection of insulin and FGF2, we found an area of BrdU/PCNA-labeled cells, ~700 µm wide, near the retinal margin (Figs. 2b,f). We also found many cells labeled for PCNA alone extending ~1000 µm into the retina (Fig. 2b,f). When BrdU was injected 24 hr after the final injection of insulin and FGF2, we observed numerous BrdU/PCNA-labeled cells that extended over 1 mm into the retina (Fig. 2c,g). When BrdU was injected 48 hr after the final injection of insulin and FGF2, we observed relatively few BrdU-labeled cells scattered across the retina, whereas numerous PCNA-labeled cells were found scattered within the peripheral retina ~2.5 mm from the retinal margin (Fig. 2d). With increasing time after the final injection of insulin and FGF2, the region in which BrdU- and PCNA-labeled cells were observed increased in size, spreading from the far peripheral retina toward more central regions. The greatest number of BrdU-labeled cells appeared when BrdU was applied 24 hr after the final injection of growth factors (164.3 ± 25.4 cells per section) (Fig. 2c), compared with numbers observed when BrdU was applied at 6 hr (38.8 ± 8.5 cells per section), 12 hr (63.1 ± 12.7 cells per section), or 48 hr (59.5 ± 21.2 cells per section). Together, these findings indicate that three consecutive daily injections of insulin and FGF2 induce a wave of proliferating cells that begins at the retinal margin and propagates several millimeters toward central regions of the retina.
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Figure 2. Insulin and FGF2 induce a wave of proliferating cells that begins at the retinal margin and proceeds toward central regions of the retina. Vertical sections of the retina were labeled with antibodies to PCNA (in red) and BrdU (in green). Cells double labeled for PCNA and BrdU appear yellow, because all BrdU-labeled cells express PCNA. a-d, Retinas were obtained from eyes that received three consecutive daily injections of insulin and FGF2 (without BrdU). Injections of growth factors were made from P7 through P9, and a single injection of BrdU was made at 6 hr (a), 12 hr (b), 24 hr (c), or 48 hr (d) after the final injection of growth factors. Eyes were harvested 6 hr (a), 12 hr (b), or 24 hr (c, d) after the injection of BrdU. e-g, Images are enlarged from the areas boxed out in green in a-d. Arrows, Retinal margin. Scale bars: c (for a-c), 200 µm; g (for e-g), 50 µm. GCL, Ganglion cell layer.
Because we observed proliferating cells only in retinas that received three, but not two, consecutive daily doses of insulin and FGF2, we sought to test whether this was a cumulative effect. These three doses would have totaled 6 µg of insulin and 300 ng of FGF2 delivered to an eye. Accordingly, we gave a single large injection of insulin (6 µg) and FGF2 (500 ng) and harvested the eyes 24 hr later. We found that a single large dose of insulin and FGF2 did not stimulate the proliferation of cells within the retina. This finding suggests that repeated low doses or sustained levels of insulin and FGF2 are required to stimulate the proliferation of cells within the retina.
Because EGF has been shown to stimulate the proliferation of progenitors at the retinal margin of chickens (Fischer and Reh, 2000
Insulin and FGF2 induce the accumulation of progenitor-like cells within peripheral regions of the retina
To test whether progenitor cells accumulated in peripheral regions of growth factor-treated retinas, we double labeled sections with the antibodies Pax6 and Chx10. These homeodomain transcription factors are known to be coexpressed by embryonic retinal progenitors (Belecky-Adams et al., 1997
In saline-treated retinas, Pax6/Chx10-coexpressing cells were observed only at the retinal margin (data not shown), consistent with our previous report (Fischer and Reh, 2000
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Figure 3. Insulin and FGF2 induce the accumulation of progenitor-like cells that coexpress Pax6 and Chx10 in the retina. Retinas were treated with three consecutive injections of insulin (a, b) or insulin and FGF2 (c-f). Retinas were processed for immunocytochemistry 24 hr (a-d) or 10 d (e, f) after the final injection. Cells labeled for Pax6 alone are green, cells labeled for Chx10 alone are red, and cells labeled for both Pax6 and Chx10 are yellow-orange. The yellow rectangles in c and f are enlarged in d and e, respectively. The small arrows in d and e indicate cells double labeled for Pax6 and Chx10. Scale bars: c (for a, c), d (for b, d, e), 50 µm. GCL, Ganglion cell layer.
Müller glia proliferate and express Pax6 in response to insulin and FGF2
The patterns of labeling for BrdU, Pax6, and Chx10 are similar to those observed in toxin-treated retinas, where Müller glia give rise to proliferating progenitor-like cells (Fischer and Reh, 2001a
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Figure 4. Insulin and FGF2 stimulate Müller glia to re-enter the cell cycle and express PCNA and Pax6. Eyes received three consecutive daily injections of insulin and FGF2 (a-i, m-o) or insulin alone (j-l), and tissues were harvested 6 hr after the final injection. a-f, Vertical sections of the retina that were labeled for GS (in red) and BrdU (in green) (a, c) or PCNA (in green) (d, f) are shown. Small arrows, Cells that are double labeled for GS and BrdU (a-c) or GS and PCNA (d-f). Arrows, Cells double labeled for GS and BrdU or PCNA; arrowheads, cells labeled for GS alone. g-i, Vertical sections of the retina that were labeled for BrdU (in green) and Pax6 (in red). Arrows, Cells that are double labeled for BrdU and Pax6. j-l, Vertical sections of the retina that were labeled for Pax6 (in green) and GS (in red). Arrows, Cells that were double labeled for Pax6 and GS. Scale bars: c (for a-c), o (for d-o), 50 µm. GCL, Ganglion cell layer.
Because we observed the accumulation of Pax6/Chx10-coexpressing cells within the retina, we tested whether BrdU-labeled cells expressed Pax6. In retinas treated with insulin and FGF2, some of the BrdU-labeled cells in the INL and ONL were immunoreactive for Pax6 (Fig. 3g-i). Although the high density of Pax6/BrdU labeling in the INL made it difficult to clearly distinguish double-labeled cells, we were able to determine that 90.7% (137 of 151 counted from four individuals) of the BrdU-labeled cells in the ONL were colabeled for Pax6. The identity of the BrdU-positive/Pax6-negative cells remains uncertain. Of the Pax6-labeled cells in the ONL, 45.5 ± 10.7% (mean ± SE) (127 of 300 cells counted from four individuals) were labeled for BrdU, suggesting that some of the Pax6-expressing cells in the ONL may not have been dividing, or that these cells were in S phase at a time when BrdU was no longer present in the eye.
We tested whether the combination of insulin and FGF2 stimulates Müller glia proliferation and subsequent transformation into progenitor-like cells in older animals by starting the injection paradigm at P24 instead of P7. Similar to the effects of insulin and FGF2 in younger animals, we observed cells in peripheral regions of the retina that were labeled for BrdU, PCNA, Pax6, and Chx10 (data not shown).
Identification of newly generated cells in the retina
The proliferation of Müller glia after injection of insulin and FGF2 was similar to that reported for Müller glia in toxin-damaged retinas (Fischer and Reh, 2001a
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Figure 5. Some of the proliferating cells in growth factor-treated retinas differentiate into Müller glia or neurons, whereas most remain undifferentiated with continued expression of Pax6. Vertical sections of the retina were labeled with antibodies to BrdU (a, d, g, j, m) and GS (b), Pax6 (e), PKC (h), Hu (k), or calretinin (n). c, f, i, l, o, Overlay images of the panels immediately to their left. Arrows, Double-labeled cells. GCL, ganglion cell layer. Scale bars: i (for d-i), o (for a-c, j-o), 50 µm.
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Figure 6. Histogram illustrating the relative percentages of cell types that were labeled with BrdU 14 d after the final injection of growth factors. Retinas were obtained from eyes that received three consecutive daily injections of insulin and FGF2. Cell counts were made on vertical retinal sections that were immunolabeled for BrdU and Pax6, GS, Hu, PKC, or visinin.
At 12 d after the final injection of growth factors, we found some cells that coexpressed Pax6 and GS in the INL (Fig. 7a-c) and ONL (Fig. 7d-f). Because Pax6 is expressed by horizontal and amacrine cells in the INL, we surveyed the percentage of Pax6-positive cells that expressed GS in the ONL. We found that 35.6 ± 11.1% of the Pax6-labeled cells in the ONL were colabeled with antibodies to GS (83 cells surveyed from four individuals).
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Figure 7. Twelve days after the final injection of insulin and FGF2, cells in the outer and inner nuclear layers coexpress GS and Pax6. Vertical sections of the retina were labeled with antibodies to GS (a, d) and Pax6 (b, e). Retinas were obtained from eyes 12 d after the last of three consecutive daily injections of insulin and FGF2 starting at P7. Arrows, Cells double labeled for GS and Pax6; large arrowheads, cells that are labeled for Pax6 alone. Scale bars: c (for a-c), f (for d-f), 50 µm. OPL, Outer plexiform layer.
Labeling for apoptotic cells
Because the response of Müller glia to insulin and FGF2 was similar to that observed with neurotoxic damage, we tested whether intraocular injections of growth factors induced programmed cell death. We probed for fragmented DNA by using the terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) method at 6 hr, 12 hr, 1 d, 2 d, or 3 d after the final injection. One, two, or three consecutive daily applications of insulin alone (Fig. 8a), FGF2 alone (Fig. 8b), or insulin and FGF2 (Fig. 8c) did not induce TUNEL-labeled nuclei at the retinal margin or in more central regions of the retina at any time after the final injection. These findings indicate that the proliferation and transdifferentiation of Müller glia induced by exogenous insulin and FGF2 were not secondary to damage to retinal neurons.
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Figure 8. Apoptotic nuclei were not found in retinas treated with growth factors. Vertical sections of the peripheral retina were obtained from eyes that received three consecutive daily doses of insulin alone (a), FGF2 alone (b), or insulin and FGF2 (c). Apoptotic nuclei were not detected at any time (6, 24, or 48 hr) after the final injection of insulin and FGF2. GCL, Ganglion cell layer. Scale bars: b (for a, b), c, 50 µm.
DISCUSSION
Here we report that exogenous insulin and FGF2 induce a response in Müller glia that is similar to that observed after neurotoxic damage. We found that insulin and FGF2 (1) suppressed the expression of GS by Müller glia, (2) stimulated Müller glia to express Pax6 and PCNA, (3) induced the accumulation of progenitor-like cells in peripheral regions of the retina, (4) stimulated Müller glia to re-enter the cell cycle within 2 d after the final injection of growth factors, and (5) stimulated the production of new glia and neurons within peripheral regions of the retina. These results are summarized in Figure 9. All of these effects were observed in the absence of retinal damage, as indicated by the absence of TUNEL-labeled cells.
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Figure 9. Diagrams summarizing the responses of Müller glia to intraocular injections of insulin and FGF2 and the region of the retina in which the responses occur. The thickness of the retina is not drawn to scale in the top panel, whereas the radial diameter matches the scale bar (500 µm). CMZ, Ciliary marginal zone; GCL, ganglion cell layer.
In response to insulin and FGF2, proliferating Müller glia rapidly downregulate their expression of GS. Similarly, in toxin-treated eyes, we have reported that BrdU labeling first appears in GS-positive Müller glia that express neurofilament, and, subsequently, these cells downregulate their expression of GS (Fischer and Reh, 2001a
We propose that the proliferating progenitor-like cells that accumulated in peripheral regions of the retina were derived from Müller glia. Shortly after the last of three consecutive daily injections of insulin and FGF2, we observed numerous GS-expressing Müller glia that accumulated BrdU and expressed PCNA and Pax6. Twenty-four hours after the final injection of growth factor, we found that all of the Pax6-expressing cells that accumulated in the ONL coexpressed Chx10, suggesting that the Pax6/GS-positive cells observed ~18 hr earlier had migrated into the ONL and turned on Chx10. This result is reminiscent of the response of Müller glia in toxin-damaged chick retina (Fischer and Reh, 2001a
The significance of Pax6/GS-expressing cells remains uncertain. Twelve days after the final injection of insulin and FGF2, we found that approximately one-third of the Pax6-labeled cells in the ONL expressed GS, whereas the majority of Pax6 cells did not. GS-expressing Müller glia normally do not express Pax6 (Fig. 4); therefore, the Pax6/GS-expressing cells may not be Müller glia. Aside from glial cells, GS may be expressed at low levels by progenitor cells in the embryonic chick retina. For example, Linser et al. (1997)
Injections of growth factors caused the generation of some new neurons. These new neurons in peripheral regions of the retina could have been produced by progenitors at the retinal margin, quiescent stem cells seeded within the retina, or Müller glia. It is unlikely that newly generated neurons within the retina were derived from progenitors at the retinal margin. The neurons were found between 0.2 and 2 mm away from the retinal margin, well past the region where BrdU-labeled cells derived from progenitors at the margin accumulate in retinas treated with insulin alone (Fischer and Reh, 2000
The combination of insulin and FGF2 was required to stimulate Müller glia to dedifferentiate and become progenitor-like cells. The combination of these factors seems to be required for several different phenomena in the avian retina. In the postnatal chick eye, we have reported recently that the combination of insulin and FGF2 induces the production of ganglion cells from progenitors at the retinal margin (Fischer et al., 2002
It remains uncertain why Müller glia in peripheral regions of retina are more responsive to insulin and FGF2 than Müller glia in central regions of retina. During embryonic retinal histogenesis, Müller glia in central regions of the retina are produced before those in peripheral regions (Prada et al., 1991
The ability of glia to generate new neurons has been addressed by several recent studies. Recent reports have demonstrated that during embryonic development, proliferating "radial glia" produce new neurons and astrocytes (Malatesta et al., 2000
FOOTNOTES Received May 31, 2002; revised Aug. 12, 2002; accepted Aug. 23, 2002.
This work was supported by fellowships from the Alberta Heritage Foundation for Medical Research and the Canadian Institutes of Health Research (A.J.F.) and by National Institutes of Health Grant R01 EY13475 and National Science Foundation Grant 1BN 9604843 (T.A.R.). We thank Josh Friedland-Little for providing expert technical assistance. We also thank Drs. D. Raible and R. Kubota for their comments that helped to contribute to the final form of this manuscript. The Pax6 and BrdU antibodies developed by Drs. A. Kawakami and S. J. Kaufman, respectively, were obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the National Institute of Child Health and Human Development and maintained by the Department of Biological Sciences, University of Iowa (Iowa City, Iowa).
Correspondence should be addressed to Dr. Thomas A. Reh, Department of Biological Structure, University of Washington, Box 357420, Seattle, WA 98195. E-mail: tomreh{at}u.washington.edu.
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