Department of Neurobiology, E1440 Biomedical Science Tower, Pittsburgh, PA 15261, USA
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Abstract |
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Introduction |
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Materials and Methods |
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Results and Discussion |
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In recent years, an increasing number of molecules have been shown to exhibit restricted patterns of expression, such that they are localized in discrete regions of the cerebral cortex [for review see Levitt (Levitt, 1999)]. The limbic system-associated membrane protein (LAMP) is expressed by most neurons in the developing and adult limbic cortex, including perirhinal, cingulate and prefrontal, with little to no expression in non-limbic cortical regions, such as somatosensory and visual (Levitt, 1984
; Horton and Levitt, 1988
; Pimenta et al., 1996
; Reinoso et al., 1996
). In contrast, neurotrimin, a related member of the Ig superfamily, is expressed in primary sensory areas (Struyket al., 1995;
Gil et al., 1997
). Similar complementary patterns of expression by members of the same family of molecules have been described. For example, within the cadherin family, cad-6 and cad-8 are expressed in the parietal and limbic cortices, respectively (Redies and Takeichi, 1996
). The Eph receptor A5 is found in limbic cortical regions (Zhang et al., 1997
) while its ligand, Ephrin-A5, is most heavily expressed in primary somatosensory cortex (Gao et al., 1998; Mackarehtschian et al., 1999
). Interestingly, all the molecules thus far described have been implicated in axon guidance and thus may mediate the formation of cortical circuits during development. In fact, the early establishment of regional differences in the expression of such guidance molecules may underlie the precision that is seen in the assembly of the initial corticocortical and thalamocortical connections. There are other molecules whose role in cortical development is unknown at this time, but also are distributed in a spatially restricted manner. For example, latexin expression is limited to neurons in the infragranular layers of the lateral cerebral cortex (Arimatsu et al., 1992
, 1994
), while an enhancertrap transgenic line has been isolated that expresses the lacZ reporter gene specifically in layer IV neurons in the somatosensory cortex (Cohen-Tannoudji et al., 1994
).
Regulation of Region-specific Gene Expression
As seen above, within the cerebral cortex many molecules are expressed in unique patterns that often reflect distinct anatomical or functional domains. It is difficult to determine in vivo, however, the precise stage at which a cortical cell becomes restricted to a particular regional fate. In addition, little is know about the specific molecular signals that impact on the decision of an individual cortical progenitor to adopt its final regional fate. To address such issues, we established an in vitro system in which progenitor cells are isolated from different anteroposterior and mediolateral domains of the cerebral wall at E12 in the rat (Ferri and Levitt, 1993). At this stage of corticogenesis, most progenitors are mitotically active, although neurons destined for the preplate are being generated (Bayer and Altman, 1991
). The cortical progenitors are grown at low density for 4 days and gene expression in response to a variety of defined extracellular signals is monitored (Ferri and Levitt, 1995
; Ferri et al., 1996
; Eagleson et al., 1997
, 1998
). We have characterized extensively these cultures of early progenitors and demonstrated, using BrdU labeling, that in the absence of exogenous growth factors the pattern of proliferation is similar on a variety of substrates: mitotic activity is always highest during the first 24 h in vitro, with little cell division occurring after 48 h (Ferri et al., 1996
). Furthermore, both TUJ1 (unpublished observations) and MAP2 immunocytochemistry (Ferri and Levitt, 1993
, 1995
) reveals that by 96 h neuronal differentiation is essentially complete. Using this culture paradigm, we demonstrated that neuronal progenitors are fated to a limbic or non-limbic phenotype, defined by the expression of LAMP, depending on their tangential location in the ventricular zone (Ferri and Levitt, 1993
). Thus, most progenitors from the presumptive perirhinal (limbic) portion of the cerebral wall express LAMP upon differentiation in vitro, while, under the same culture conditions, few precursors from the presumptive sensorimotor or visual (non-limbic) regions express this protein. A series of explant studies has demonstrated a similar early fate of lateral and medial regions of the cerebral wall (Arimatsu et al., 1992
). Explants of the lateral wall become latexin-positive after several days in vitro. Those explants derived from more medial regions of the cerebral wall, however, never express this protein. The pattern of latexin expression in these explants reflects the distribution of this protein within the cerebral cortex in vivo (Arimatsu et al., 1992
; Arimatsu and Ishida, 1998
). It should be emphasized that in all these studies, the cortical progenitors are isolated at least 23 days before LAMP or latexin expression in vivo and prior to thalamocortical and corticocortical interactions. These observations are consistent with the hypothesis that the regional specification of cortex, as measured by the commitment to differential gene expression, occurs early during corticogenesis, probably within the ventricular zone (Rakic, 1988
; Barbe and Levitt, 1991
; Arimatsu et al., 1992
; Ferri and Levitt, 1993
; Cohen-Tannoudji et al., 1994
; Levitt et al., 1997
).
The early commitment of cortical progenitors to a particular areal fate does not preclude the later acquisition by post-mitotic neurons of other phenotypic traits. We used the same culture paradigm described above to examine the stage at which somatosensory cortex first becomes fated to express ephrin-A5 protein. We stained cultures with an alkaline phosphatase-tagged EphA5 extracellular domain fusion protein. In cultures isolated from the later stages of corticogenesis (E16/17 in the rat), the majority of cells from the somatosensory cortex express ephrin-A5 (Fig. 1), while only a few cells from the visual cortex express this protein (data not shown). In contrast to the observations with LAMP and latexin, however, progenitors derived from earlier stages of corticogenesis (E12) fail to express ephrin-A5 upon differentiation into neurons, regardless of the region of the ventricular zone from which they were isolated (Fig. 1
). Recently, ephrin-A5 message has been detected as early as E11 in the rat in progenitor cells within the ventricular zone of the telencephalon (Mackarehtschian et al., 1999
); the signal, however, is abundant in the most anterior region, that gives rise to the olfactory bulb, with little to no signal in the more posterior areas that include the presumptive sensorimotor and visual cortices. Indeed, more robust ephrin-A5 expression in sensorimotor cortex is not observed until around E17 and is confined to regions outside of the proliferative zones, while at all stages only low to no expression is seen in visual cortex. These observations, together with our cell culture results, suggest that the expression of ephrin-A5 within the cerebral wall, at least in the subplate and cortical plate proper, is likely to be regulated by signals that arise later in development once the progenitor has exited the cell cycle. We cannot, however, exclude the possibility that there is heterogeneity within the ventricular zone with respect to their potential to generate ephrin A5 expressing neurons.
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To understand more fully the mechanisms that underlie the acquisition of a limbic fate, we examined the relationship of cell fate to cell lineage (Eagleson et al., 1997, 1998
). In these experiments, we utilized cortical progenitors isolated from the fronto-parietal regions of the cerebral wall that includes both presumptive limbic and non-limbic areas. To follow the fate of individual progenitor cells, the cortices were infected immediately following dissociation with a replication-incompetent retrovirus vector that transduces the bacterial lacZ gene encoding ß-galactosidase. Such retroviruses integrate into post-replication DNA of dividing precursor cells; thus, ß-galactosidase is expressed in only one of the daughter cells following mitosis (Hajihosseini et al., 1993
; Roe et al., 1993
). If this daughter cell enters Go and becomes post-mitotic, a single-cell clone is produced; progression through at least one additional, complete cell cycle results in a multicell clone. When grown in the presence of the inductive signals, on collagen type IV with either TGF
or neuregulin, there was no effect on the size distribution of the clones or the number of labeled clones per coverslip (Eagleson et al., 1997
, 1998
). This is consistent with previous observations that activation of the EGF receptor by either EGF or TGF
has no effect on the proliferative behavior of early cortical progenitors (Kilpatrick and Bartlett, 1995
; Ferri et al., 1996
). In addition, in our culture system both the total number of neurons (Ferri and Levitt, 1995
) and the number of neuronal clones (Eagleson et al., 1997
) is the same in both inducing and non-inducing conditions. This suggests that TGF
and neuregulin do not affect the choice between a neuronal and glial fate but rather influence the regional phenotype adopted by an already committed neuronal progenitor. This contrasts with later stages in corticogenesis, when both TGF
and neuregulin are known to have mitotic activity (Kilpatrick and Bartlett, 1995
) as well as a role in gliogenesis (Cannoll et al., 1996
; Burrows et al., 1997
). It also highlights the changing nature of cortical progenitor cells with developmental time (Burrows et al., 1997
; Lillien, 1998
). Together, the observations outlined above indicate that it is unlikely that either selective proliferation or cell death plays a significant role in determining the proportion of neurons that express LAMP under inducing or non-inducing conditions.
The clonal studies revealed several interesting features of area specification (Eagleson et al., 1997, 1998
). First, clones are almost entirely homogeneous, containing LAMP-positive or LAMP-negative cells only. Furthermore, even in the non-inductive environment, there are numerous multicell, LAMP-positive clones. This suggests that cortical progenitors that receive the limbic-inductive signal in vivo are able to retain the memory of this signal through several rounds of division in the absence of the signal. Second, while multicell neuronal clones express LAMP in the presence of the inductive signal, single cell clones do not. As described earlier, the single cell clones represent progenitors that were already progressing through their final cell cycle at the time of plating. Thus, specification of a limbic fate is dependent upon the cortical progenitors receiving the appropriate inductive signal for a least one complete cell cycle, a requirement that is the same for both TGF
and neuregulin. It should be noted, however, that while all neuronal multicell clones respond to TGF
, only half respond to neuregulin, highlighting the heterogeneous response of cortical progenitors to these growth factors. Furthermore, these results predict that addition of the growth factor for only part of the cell cycle, or once the neurons are post-mitotic, should not affect LAMP expression by non-limbic progenitors. This is indeed the case: if either growth factor is present for only the first 5 h (the cell cycle takes at least 810 h at this stage) or after 60 h (when there is no cell proliferation), LAMP is not induced in neurons obtained from non-limbic regions of the wall (Ferri and Levitt 1995
; Ferri et al., 1996
; Eagleson et al., 1998
). Third, a similar clonal analysis was performed on cortical progenitors isolated at later stages of corticogenesis in the rat: E14, at which time neurons destined for layers VI through IV are being produced, and E16, when layers III and II are being generated (Bayer and Altman, 1991
). The pattern of inductive behavior is similar to that observed in neuronal clones isolated from the E12 cerebral wall (Eagleson et al., 1997
), indicating that cortical progenitors throughout the entire period of neuron production in the cerebral wall remain competent and respond to the LAMP-inductive signal. In contrast, the laminar potential of cortical progenitors changes with age, such that at later stages of corticogenesis the progenitors are restricted to an upper-layer fate (Frantz and McConnell, 1996
). At E16, however, there is a small group of multicell neuronal clones that do not respond to TGF
/collagen type IV and these may represent superficial neurons that normally do not express LAMP in limbic cortex.
A recent series of experiments examining the regulation of latexin expression during development (Arimatsu et al., 1999) has demonstrated an additional mechanism for generating regionally restricted phenotypes within the cerebral cortex. During early corticogenesis (E13 in the rat), there is already a restricted distribution, within the ventricular zone, of progenitors that possess the capacity to generate latexin-positive neurons. Competent progenitors reside only in the lateral regions of the cerebral wall, while those located more dorsally have lost the potential to express latexin. In contrast to LAMP expression, however, these progenitors, upon differentiation into neurons, require exposure to an appropriate environmental signal before they express latexin; neurons that do not receive this signal fail to express the protein. The competence to respond to this signal appears to be lost in the early postnatal period. Furthermore, although the specific signal required for latexin expression has not yet been identified, there is evidence that it is present in lateral, but not medial, cerebral cortex for a restricted period during late embryogenesis.
Cortical Progenitor Cells are Heterogeneous
The profile of LAMP expression, in the presence or absence of TGF and neuregulin, reveals a heterogeneity in the responsiveness of non-limbic cortical progenitors to different growth factors (see above) (Eagleson et al., 1998
). There is considerable evidence that the pattern of receptor activation and signal transduction stimulated by the erbB receptor ligands depend upon the combination of erbB receptors expressed by progenitors. For example, the members of the erbB family are able to form heterodimers (Carraway and Cantley, 1994
; Qian et al., 1994
; Earp et al., 1995
; Karunagaran et al., 1996
; Kramarski et al., 1996
; Pinkas-Kramarski et al., 1996
; Graus-Porta et al., 1997
), with the choice of co-receptor dependent upon strict hierarchical rules (Tzahar et al., 1996
, 1997
). Furthermore, different receptor dimers couple with distinct signaling pathways (Kim et al., 1994
; Soltoff et al., 1994
; Fedi et al., 1994
; Levkowitz et al., 1996
). We have used a double-label immunocytochemistry strategy in our culture system to test the hypothesis that the heterogeneous responsiveness of non-limbic cortical progenitors to TGF
and neuregulin reflects the expression of different repertoires of the erbB receptor family (Eagleson et al., 1998
). At 5 h, when most progenitors are mitotically active, subpopulations of progenitor cells express the EGF receptor alone, erbB3 alone, or both the EGF receptor and erbB3. Additionally, ~20% of cells express neither receptor, a similar percentage to those that do not respond to either TGF
or neuregulin and most likely represent neuronal progenitors that are post-mitotic at the time of plating. A similar profile is seen for the EGF receptor and erbB4. By 48 h in vitro, however, a time when all neuronal progenitors are post-mitotic and unable to respond to the LAMP-inductive signals (Ferri and Levitt, 1995
; Ferri et al., 1996
; Eagleson et al., 1997
), a different pattern emerges. At this time, most cells do not express either the EGF receptor or erbB3, but many continue to express erbB4. The down-regulation of the EGF receptor and erbB3 is already apparent by 24 h, suggesting that this decrease may be correlated with the exit of the progenitor cells from the cell cycle. The continuing presence of erbB4 once the cell has exited the cycle, however, does not preclude a role for this receptor in the induction of a limbic fate. Indeed, there may be a change in the coupling of receptors to different signal transduction pathways as the neuron differentiates and thus different intracellular signaling may occur following ligand binding than when the cells were proliferating. This is probably also true for the EGF receptor, which is known to be expressed on post-mitotic neurons in the cortical plate (Eagleson et al., 1996
; Kornblum et al., 1997
) and is also re-expressed by neurons in our cultures at 96 h (70%, Fig. 2
); in contrast, erbB3 is low in these cultures after 24 h (%) while erbB4 continues to be expressed (78% at 96 h, Fig. 2
).
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The ability of cortical progenitor cells from widely divergent regions of the cerebral wall to respond to the LAMP-inductive signals in vitro suggests that the expression of the erbB receptors is not confined to limbic regions. Immunocyto-chemical analysis of the developing cerebral wall has shown that, at E11 and 12, the EGF, erbB3 and erbB4 receptors are expressed throughout the ventricular zone, with no obvious gradient in either the rostrocaudal or dorsoventral axes (Eagleson et al., 1996, 1998
). This is also true for collagen type IV. A more extensive analysis of the distribution of the EGF receptor and the matrix molecule throughout corticogenesis reveals that these molecules are co-expressed only in the ventricular and subventricular zones (Eagleson et al., 1996
). Thus, although the anatomical distribution of collagen type IV and the various erbB receptors is consistent with a role for these molecules in the early cell fate choices for cortical progenitors, cells in both limbic and non-limbic regions have the intrinsic capacity to respond to limbic-inductive signals. This suggests that decision-making regarding cell fate in the ventricular zone more likely involves differences in local environmental signals to which the precursors are exposed (Levitt et al., 1997
). Spatially restricting, for example, ligand availability would, in effect, limit the potential array of phenotypes expressed when the progenitors differentiate into neurons. To date, however, the anatomical distribution of the ligands for the erbB receptor family has not been examined at the protein level at early stages of cortical development that are critical for decisions being made regarding certain regional phenotypes. Nonetheless, in situ hybridization analysis demonstrates that alternatively spliced transcripts of the neuregulin-1 gene are expressed in unique patterns within the ventricular and subventricular zones (Marchionni et al., 1993
; Corfas et al., 1995
; Meyer et al., 1997
). Furthermore, the ganglionic eminence and developing striatum produce the highest levels of TGF
in the forebrain (Lazar and Blum, 1992
; Kornblum et al., 1997
) and are therefore a potential source to establish a gradient of this factor in the telencephalic wall. In fact, the higher concentrations would be present in the adjacent presumptive limbic cortices that express LAMP. The importance of spatially restricted ligands in the regulation of a particular phenotype by a limited number of competent cells has been well documented in other systems, including the developing limb bud (Laufer et al., 1994
; Kawakami et al., 1996
; Rodriguez et al., 1996
; Macias et al., 1997
; Pizette and Niswander, 1999
).
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Conclusion |
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Notes |
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Address correspondence to Pat Levitt, Department of Neurobiology, E1440 BSTWR, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. Email: plevitt+{at}pitt.edu.
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References |
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