1 Center for Neurobiology and Behavior, Departments of , 2 Neurology and , 3 Pathology and the , 4 Sergievsky Center, Columbia University College of Physicians and Surgeons, 630 W. 168th Street, New York, NY 10032, USA
Address correspondence to Arnold Kriegstein, 630 W. 168th St., P&S Bldg. Room 4-408/Box 31, New York, NY 10032, USA. Email: ark17{at}columbia.edu.
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Abstract |
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Introduction |
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The discovery of a neurogenic role for radial glia alters traditional views of cortical development. This does not rule out the possibility, however, that non-radial glial neuronal precursors may contribute to neurogenesis as well. This possibility was recently examined using several different strategies (Götz et al., 2002; Noctor et al., 2002
). Since birthdate labeling experiments indicate that cortical neurons arise from mitotic cells within the VZ during a discrete developmental period (Bayer and Altman, 1995
), we determined what proportion of the cells undergoing mitosis at these ages are radial glia. Cells in S-phase and M-phase were analyzed separately. S-phase cells were identified with BrdU pulse-labeling, and counts were made of how many mitotically active cells were labeled by the radial glial markers vimentin and RC2. At early, middle and late periods of rat cortical neurogenesis, essentially all S-phase cells expressed these markers (99.3 ± 0.3% at E12; 98.6 ± 0.5% at E15; and 98.3 ± 0.4% at E18). Moreover, using retrograde transport of fluorescently tagged microspheres we found that most cells (90.5 ± 2.5%) in S-phase also made contact with the pial surface, a morphological feature that helps to define radial glia. Furthermore, we determined the percentage of cells undergoing cytokinesis that also expressed a radial glia-specific mitotic marker, phosphorylated vimentin [4A4 antibody (Kamei et al., 1998
)]. Once again, essentially all VZ cells in mitosis expressed this radial glial cell marker (98.7 ± 0.1% at E12; 98.3 ± 0.3% at E15; and 98.8 ± 0.1% at E18). Cells labeled by 4A4 were also observed to have radial fibers extending toward and in many cases reaching the pia, additionally confirming their identification as radial glia [see also Kamei et al. (Kamei et al., 1998
)]. These data indicate that the majority of dividing VZ precursor cells in the rodent are radial glia. Together with work from Götz and colleagues (Götz et al., 2002
), this leads to the hypothesis that most cortical neurons may therefore derive from radial glial cells. However, it is also likely that radial glia are heterogeneous in terms of the types of progeny that they may produce. Retroviral lineage experiments have suggested that progenitors may give rise to distinctly different clones of neuronal or glial progeny (Parnavelas et al., 1991
; Luskin et al., 1993
), and subsets of radial glia express different sets of molecular markers (Hartfuss et al., 2001
). Therefore, while the majority of cortical neuronal progenitor cells may be radial glia, radial glia likely represent a diverse class of precursor cell, heterogeneous in terms of molecular expression and germative potential.
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Neurogenic Radial Glia: a Common Theme among Vertebrates |
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Radial Glial Cells May Also Be Neuronal Progenitors in Human Cortex |
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Cortical neurogenesis occurs by mitosis of progenitor cells at the ventricular surface. We therefore examined the proportion of mitotic cells in the human VZ that express radial glial proteins. The intermediate filament marker, vimentin, is expressed by rodent radial glia and is phosphorylated during M-phase. Therefore, as mentioned above, anti-phosphorylated vimentin (4A4) antibody has been used as a marker of mitotic radial glia in rodent brain (Kamei et al., 1998; Götz et al., 2002
; Noctor et al., 2002
). Because human radial glial cells also express vimentin at early stages of cortical development (Stagaard and Mollgard, 1989
; Honig et al., 1996
), we examined whether the 4A4 antibody would label dividing human radial glia. We obtained fixed, coronal brain slices from gestational age 14 week human cortex and incubated them in anti-phosphorylated vimentin (4A4) with one of three nuclear markers: anti-Ki-67, anti-phospho-histone H3, or human anti-kinetochore antiserum. Anti-Ki-67 labels a nuclear transcription factor expressed from S-phase through M-phase; H3 labels a histone phosphorylated from G2 to early telophase; and the anti-kinetochore antibody labels condensed chromatin, thereby identifying cells exclusively within M-phase (Fig. 2E
). We found that the 4A4 antibody was effective in labeling mitotic human radial glia. As expected, the 4A4-labeled cells were arrayed along the ventricular surface (Fig. 2AC
). We next identified M-phase cells at the ventricular surface using one of the three M-phase markers and examined whether these cells were double-labeled with the anti-phosphorylated vimentin antibody (4A4) using confocal microscopy. Ki-67 antigen expression begins during S-phase, continues through G2 and M-phase, and becomes nearly undetectable at the beginning of G1 (Fig. 2E
) (Scholzen and Gerdes, 2000
). Since 4A4 specifically labels cells in M-phase, we would expect to find double-labeled M-phase cells as well as Ki-67-positive cells that have not yet entered M-phase, and thus would not be 4A4-immunoreactive. Consistent with this prediction, we found that 38% of Ki-67-positive cells were labeled by the radial glial antibody 4A4 (Fig. 2A,D
). Since we observed only partial overlap of these two markers, we next evaluated co-labeling of 4A4 with the phospho-histone H3, which has a more restricted expression pattern (Fig. 2E
). H3 is phosphorylated during late G2 and dephosphorylated during mitosis [anaphase to telophase (Hendzel et al., 1997
)]. We therefore would expect a greater overlap with these two markers than that seen with Ki-67. We observed that 61% of H3-positive cells were 4A4-positive, consistent with the prediction that many dividing human VZ cells express the phosphorylated form of the radial glial vimentin protein during M-phase (Fig. 2B,D
). We next determined how M-phase-specific 4A4 labeling overlaps with a more restricted kinetochore marker that is specific to M-phase (Fig. 2E
). Since the anti-kinetochore antibody identifies the condensed chromatin of all cells in M-phase, we would expect a tight overlap with 4A4 labeling. We found that 92% of M-phase cells in the human VZ with condensed chromatin expressed the radial glial marker, 4A4 (Fig. 2C,D
). These data indicate that in the human, as in the rodent, at an embryonic age when a large number of neurons are being born in the VZ, radial glia-specific proteins are expressed by most mitotically active cells. This expression pattern raises the possibility that radial glial cells may act as neuronal progenitors in the human VZ.
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Radial Glial Fiber Morphology during Cell Division |
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Our own data suggest that a radial fiber is maintained through all stages of division. This is consistent with recent work from others as well (Miyata et al., 2001; Götz et al., 2002
). We labeled rat VZ cells in fixed tissue (E16E20) by applying DiI to the pia, and observed labeled cells in various mitotic stages, suggesting that cells may not lose contact with the pia during division (Fig. 3AC
). We have observed that when radial glial cells round up to divide, radial fibers become extremely thin and form small varicosities [Fig. 3
; see also Miyata et al. (Miyata et al., 2001
)]. Interestingly, thin fibers labeled with DiI are often quite dim, suggesting that they remain connected to the pia but their contact may become limited during this stage. Thin fibers may therefore have been missed in previous EM studies, and may in fact remain extended to the pia throughout all stages of mitosis (Miyata et al., 2001
; Götz et al., 2002
; Noctor et al., 2002
).
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Two Alternative Modes of Radial Glial Guided Neuronal Migration |
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To examine the behavior of radial glial progeny we performed a lineage analysis using a green fluorescent protein (GFP)-expressing retrovirus that was injected in utero to infect mitotic cells (Noctor et al., 2001). If a majority of neurons undergo somal translocation to the cortex, we reasoned that many of the progeny of a radial glia-derived clone should exhibit pial endfeet, since each neuron would remain in contact with the external limiting membrane while translocating to the top of the cortical plate. However, in our GFP-labeled radial clones, we typically observed only one radial fiber per clone, and that fiber appeared to belong to the radial glial cell based on intracellular dye filling (Noctor et al., 2001
). Therefore, in retrovirally labeled clones in vivo, we have not observed that a majority of neurons undergo translocation. Presumed migrating neurons have short leading and trailing processes, suggesting that these cells are locomoting rather than translocating. Figure 5A
shows the typical morphology of migrating neurons observed in retrovirally labeled clones. There is a possibility, however, that our GFP labeling method fails to identify translocating clones, possibly as a result of the ages that we infect (E1518), or by virtue of viral selectivity. We therefore used a different labeling technique to address whether or not a large number of neurons undergo somal translocation.
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Conclusions |
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Historically there has been some question as to whether radial glial cells maintain radial fibers during division. In general, it was not accepted that a differentiated cell type such as the radial glial cell could divide without retracting its elaborate pial process, although other cell types are known to undergo mitosis without rounding up completely (Wolf et al., 1997). Recent work suggests that radial glial fibers are maintained during cell division (Miyata et al., 2001
; Noctor et al., 2001
; Götz et al., 2002
), and we show here that in dividing VZ cells, a vimentin-positive radial fiber is present throughout each stage of mitosis. These data suggest that radial glial cells do not become completely spherical during mitosis, as was historically described for cells dividing at the ventricular surface. Rather, the somal portion of the cell, present at the ventricular edge, rounds and enlarges, likely due to cytoplasm streaming down from the radial fiber (Miyata et al., 2001
). The fiber remains elongated; however, it is pinched off and dramatically thins distal to a short radial stub projecting from the soma (Fig. 4E
). During telophase this stub appears to distribute asymmetrically by associating specifically with one of the two daughter cells (Fig. 4IM
). Following telophase, the thinned fiber quickly refills with cytoplasm that streams radially from the cell body (Miyata et al., 2001
; Noctor et al., 2001
). Retention of the radial fiber during cell division helps to explain how the radial fiber of a mitotically active cell can continually function in guiding neuronal migration.
Interestingly, the presence of a radial stub begins to question the true nature of a symmetric division. Symmetric divisions in the VZ have been described as those in which the cleavage plane (plane of the metaphase plate) is roughly perpendicular to the surface of the ventricle (vertical cleavage plane, Fig. 4AM) (Chenn and McConnell, 1995
). If radial fibers are maintained in the above manner during a vertical, symmetric division, as we show in Figure 4
, then the two daughter cells would not be truly symmetric, with one possessing the stub and the other completely round. Furthermore, McConnell and colleagues (Chenn and McConnell, 1995
) observed that as neurogenesis proceeds in the developing ferret cortex, vertical cleavages (presumed to be symmetric divisions) decreased, while horizontal cleavages (presumed to be asymmetric divisions) increased. This was consistent with the idea that vertical cleavages are symmetric divisions producing two precursor cells, while horizontal cleavages are asymmetric divisions resulting in the production of one neuron and one precursor cell. Our results, however, do not show a significant decrease in vertical cleavages during the period of neurogenesis in the rat (E12E18). Coupled with our observation of an asymmetric radial stub and fiber associated with one daughter cell during vertical division, this calls into question whether all of these divisions are truly symmetric. Our results suggest that at least some rat VZ cell divisions occurring in the vertical cleavage plane are asymmetric or result in neuronal production.
The establishment of a neurogenic role for radial glia could have implications for theories of neuronal migration. Radial migration is widely believed to involve neuronal locomotion along radial glial guides. A great deal of data has documented this mode of migration, including electron microscopic images of bipolar neurons clutching radial fibers (Rakic, 1971b), and in vitro time-lapse studies of neurons with leading and trailing processes migrating along radial glia (Edmondson and Hatten, 1987
). However, an alternative mode of migration, whereby a newborn neuron resembling a radial glial cell simply undergoes intracytoplasmic nuclear translocation from the ventricular surface to the cortical plate, has also been repeatedly described (Berry et al., 1964
; Berry and Rogers, 1965
; Morest, 1970
; Brittis et al., 1995
; Miyata et al., 2001
; Nadarajah et al., 2001
). Based on the concept of radial glial neurogenesis, it is easy to imagine how the neuronal progeny of a radial glial cell could inherit a radial process of the parental radial glial cell and be ready to promptly translocate to the cortex.
Results from Miyata and colleagues (Miyata et al., 2001), Götz and colleagues (Götz et al., 2002
), and those presented here suggest that translocation of newborn neurons appears to occur at least part of the time during cortical development. What factors might determine whether neurons migrate by translocation or locomotion? One possibility is that different modes of migration predominate at progressive stages of neurogenesis. For example, translocation has been discussed as a mode of migration at early stages of corticogenesis (Morest, 1970
; Brittis et al., 1995
; Nadarajah et al., 2001
). However, our evidence suggests that translocation is not the predominant form of neuronal migration during mid to late stages of cortical development. At later stages of development, when the cortical mantle is greatly enlarged, newborn neurons may be more likely to migrate using the traditional locomotion mechanism.
Alternatively, whether a neuron undergoes translocation or locomotion neuronal migration and radial fiber inheritance may be dictated by extrinsic or intrinsic radial glial cell signals. Extracellular signals such as growth factors or neurotransmitters may bind to radial glial cell receptors and trigger downstream events that lead to asymmetric distribution of the radial fiber and critical cytoplasmic proteins. Alternatively, subpopulations of radial glial cells (Hartfuss et al., 2001) may be committed to different modes of fiber inheritance, producing radial clones that consist entirely of either translocated or locomoted neurons. Some radial glial subtypes, for example, may consistently donate their fiber to daughter cells, generating translocating neurons, while other radial glial cells may exclusively retain their radial fibers, generating neurons that locomote. In fact, a subset of radial glia express brain lipid-binding protein (Hartfuss et al., 2001
), a factor that is induced by locomoting neurons (Feng et al., 1994
), and these radial glia may represent the latter class of fiber-retaining precursor cells.
The finding that radial glial cells can function as neuronal progenitors in a variety of contexts has implications for potential signaling mechanisms between proliferating precursor cells and neuronal daughter cells in the developing cortex. VZ precursor cells have previously been shown to respond to the neuro-transmitters glutamate and GABA (LoTurco and Kriegstein, 1991; LoTurco et al., 1995
; Behar et al., 1998
). In fact, these transmitters can modulate rates of proliferation in the VZ (LoTurco et al., 1995
; Haydar et al., 2000
). Since VZ precursor cells were previously envisioned as short, VZ-contained cells, the source for GABA and glutamate was presumed to be immature neurons migrating within the VZ. However, the presence of a radial glial fiber that contacts neuronal progeny in the cortical plate raises the possibility that precursor cells may also be able to respond to neurotransmitters and other signaling factors released in developing cortical layers. Maturing neurons in the cortex may therefore signal to nearby radial glial fibers and thus modulate proliferation of their parental radial glial cells in the underlying VZ. Radial glial cells may concurrently provide trophic signals for maturing neurons. Radial glial cells have been shown to produce insulin-like growth factors (Jiang et al., 1998
) and estrogen (Forlano et al., 2001
); the release of such substances could potentially be involved in neuronal differentiation and/or the establishment of final cortical position. The role of radial glial cells may therefore extend beyond neuronal precursor and migrational guide, to also include the provision of trophic support during neuronal maturation. In this way, the parent radial glial cell would be responsible for not only generating neurons and guiding their migration into the cortex, but also for nurturing neuronal development.
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Footnotes |
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Acknowledgments |
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References |
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