Department of Neuroscience, University of Connecticut School of Medicine, Farmington, CT 06030, USA, 1 Present address: Department of Anatomy and Developmental Biology, University College London, UK
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Abstract |
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Introduction |
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Although much has been learned in the past few years about regulation of genesis and migration of cortical interneurons in rodents, information in primates is still scarce. In the monkey, diffuse expression of Dlx1 mRNA in layer I indicated that in primates, too, some cortical neurons have a subcortical origin (Zecevic and Rakic, 2001). However, in contrast to rodents, where the majority if not all cortical interneurons originate in the GE, in primates a large number of cortical interneurons seem to originate in the cortical ventricular (VZ) and subventricular (SVZ) zones (Rakic and Zecevic, 2001
; Zecevic and Rakic, 2001
; Letinic et al., 2002
). Therefore, in human brains, several proliferative zones, the GE, cortical VZ and SVZ, as well as the subpial granular layer (SGL), are potential sources of layer I neurons in later fetal development. The migratory routes of neurons from these different sources are more complex than has been recognized. For example, the SGL that is much more prominent and last longer in primates, has been suggested to serve as a conduit for late generated neurons coming from the olfactory region (Meyer and Goffinet, 1998
; Meyer and Wahle, 1999
; Zecevic and Rakic, 2001
). Moreover, here we observed a dynamic trafficking in both directions, as judged by the orientations of the leading processes of migratory interneurons, at the subcorticalcortical junction, and in the subventricular and intermediate zones of human fetal brains.
Primate CajalRetzius cells are among the first cells to appear in the primordial plexiform layer (PPL) (Meyer and Goffinet, 1998; Zecevic et al., 1999
; Meyer et al., 2000
; Zecevic and Rakic, 2001
) but their exact origin is still under investigation. Further-more, genesis of layer I neurons in primates last throughout the entire course of cortical neurogenesis, which complicates interpretation of their pedigree (Zecevic and Rakic, 2001
). The role of CajalRetzius cells in secreting the glycoprotein Reelin, which is necessary for normal migration and regular layering of cortical plate neurons, is well described (DArcangelo et al., 1995
, 1997
; Ogawa et al., 1995
; Del Rio et al., 1997
). It appears likely that several classes of CajalRetzius neurons exist, and that they have different origins (Zecevic and Rakic, 2001
; Meyer et al., 2002
).
The normal development of layer I in humans may have considerable clinical importance, since interneurons play a substantial role in the function of the cerebral cortex, and their impairment has long been suspected in some psychiatric disorders. CajalRetzius cells also have an important role during normal cortical development. Their impairment is related to developmental disorders of the human cerebral cortex with disturbed neural migration, resulting in lissencephaly and mental retardation (Rakic and Caviness, 1995; Clark et al., 1997
; Hong et al., 2000
). Additional roles for CajalRetzius cells, such as in schizophrenia (Impagnatiello et al., 1998
), or in repair of brain lesions (Super et al., 1997
) have been suggested.
In this study, using in situ hybridization and cell specific markers, we focus on various sources and possible migration routes of preplate and layer I neurons. Preliminary results have been previously reported (Rakic and Zecevic, 2001).
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Material and Methods |
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Human embryos and fetuses in three age groups, 59 gestational weeks, (g.w.; n = 8), 1113 g.w. (n = 4) and 1729 g.w. (n = 5), were obtained from legal abortions/autopsies with approval of the Ethics Committee (Table 1). Brain tissue was fixed in 4% paraformaldehyde, cryoprotected by immersion in 30% sucrose, and frozen in isopentane cooled to -70°C. Frozen embryos or brain blocks of fetuses were serially sectioned in coronal, sagittal or horizontal planes at 14 µm and used for either in situ hybridization, single and double immunohistochemical experiments, or TUNEL in situ assay.
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Antibodies (Table 2) that label interneurons (GABA, calbindin CB, calretinin CalR) were used in combination with antibodies specific for GE-generated cells, Dlx family and Nkx2.1. Two antibodies were used to label DLX: anti-DLX2 and pan-DLX (DLL) antibody that recognizes DLX1, 2, 5 and 6. Anti-Reelin antibodies were used to label CajalRetzius neurons and determine their relationship to cortical interneurons. The SMI-38 antibody reacts with the nonphosphorylated epitope of heavy neurofilaments and labels neuronal cell bodies, dendrites and some thick axons. In our human material this antibody selectively labeled Cajal Retzius cells in preplate/layer I. Anti-Golli antibody was used to label preplate neurons (Landry et al., 1998
; Hevner et al., 2001
; Tosic et al., 2002
). Antibodies to ß-III-Tubulin and microtubule-associated protein 2 (MAP2) were used to label undifferentiated and mature neurons, respectively. Antibody to proliferating cell nuclear antigen (PCNA) was used to assess cell proliferation. The list of antibodies is presented in Table 2
.
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In Situ Hybridization
Clones and Probes
Dlx2 and Nkx2.1 mouse clones were obtained from the laboratory of Dr John Rubenstein, University of California San Francisco. Sense and anti-sense riboprobes were generated by in vitro transcription, cloned downstream of SP6, T7 or T3 promoters, with the corresponding RNA polymerase in the presence of [35S]UTP (NEN Life Science Products Inc.).
Radioactive in situ hybridization of frozen human CNS sections was performed following the protocol previously described by Gall and Isackson (Gall and Isackson, 1989) with minor modifications. Frozen sections were first treated with 0.75% glycine in 0.1 M phosphate buffer (PB) for 5 min, rinsed with 0.1 M PB and transferred for 10 min into a solution of 0.25% acetic anhydride in 0.1 M triethanolamine, pH 8. Sections were then prehybridized for 2 h at 60°C in a 40% formamide, 10% dextran sulfate, 1 x Denhardtss solution (0.02% Ficoll, 0.02% polyvinylpyrrolidone, 0.1% RNase-free bovine serum albumine), 1 mg/ml yeast tRNA, 10 mM DTT, 1 mg/ml denatured and sheared salmon sperm DNA and 4 x SSC. Sections were hybridized overnight at 60°C in pre-hybridization buffer containing 35S-labeled sense or antisense RNA probe (1200 Ci/mmol). After hybridization, sections were washed in 4 x SSC (30 min, 60°C twice) and digested for 30 min at 37°C in a RNase buffer (500 m NaCl, 1 mM EDTA, 10 mM Tris-HCL, pH 7.5) containing 20 µg/ml RNase A. At the end, sections were washed in 2 x SSC (30 min, four times), 0.5 x SSC (30 min, 60°C, twice), 0.1 x SSC (15 min, twice) and DEPC-treated water (15 min). Sections were exposed to ß-max-hypersensitive film (Amersham Pharmacia Biotech Inc.) for 5 days and then dipped into NTB2 liquid emulsion (Eastman Kodak) for 5 weeks. Control sections hybridized with 35S-sense probe were not labeled above background level.
TUNEL In Situ Method
TUNEL in situ method, described previously (Rakic and Zecevic, 2000), was used to determine whether programmed cell death is responsible for SGL disappearance. In short, biotinylated dUTP molecules (Roche Molecular Biochemicals), catalyzed by terminal transferase (TdT) enzyme (Roche Molecular Biochemicals), were incorporated into nuclear DNA and visualized with a peroxidase standard Vectastain ABC kit (Vector Labs) and AEC (Vector Labs). In a negative control, the TdT enzyme step was excluded.
Definition of Anatomical Terms Used in This Study
Preplate or primordial plexiform layer (PPL) is a layer composed of afferent and efferent fibers and scattered neurons above the ventricular zone at the embryonic stages of development (58 g.w.; Carnegie stages 1422). By 8 g.w., PPL is split by the emerging cortical plate establishing layer I above and the subplate layer below the cortical plate (Zecevic, 1993; Marin-Padilla, 1998
). The subpial granular layer (SGL) is a transient, primate-specific layer of cells on top of layer I, under the pia, present in humans from 11 to 29 g.w. (Brun, 1965
; Gadisseux et al., 1992
; Meyer and Wahle, 1999
; Zecevic and Rakic, 2001
).
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Results |
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The cerebral wall at 5 g.w. embryo (Carnegie stages 1415), the earliest stage examined here, consisted only of two developmental zones: the proliferative ventricular zone (VZ), and a cell sparse PPL layer above the VZ. Neurons labeled with antibodies to ß-III-tubulin, MAP-2, Golli and calbindin were the first cells observed in the neocortical PPL (Fig. 1A red, BE). These early, radially oriented neocortical neurons in the VZ were not co-labeled with ventral transcription factors, NKX2.1 or DlX (Fig. 1G,L
), which suggested that these initial neurons have a cortical origin. In the same embryonic brain, numerous NKX2.1-positive (+) cells were present in the ventricular zone of the ventral telencephalon (preoptic area) and diencephalon (rostral hypothalamus) (Fig. 1A green, F
). NKX2.1 expression had a sharp dorsal border towards the cerebral cortex. In the region of the future hypothalamus, detached neurons contained Nkx2.1 (Fig. 1F
), showing a developmental gradient in the prosencephalon even at these initial stages of development. In contrast to this, the expression of DLX family transcription factors was spread more dorsally, into the developing cerebral cortex, up to the region of the paleocortex (Fig. 1H
). In the paleocortical PPL, the density of DLX labeled nuclei was several times bigger than in the VZ (Fig. 1K
). This was consistent with the finding that in both ventral telencephalon and ventral diencephalon, DLX was mainly expressed in the outer, non-proliferative zone (Fig. 1HJ
). DLX-expressing cells were also present outside the nervous tissue (Fig. 1H
).
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In a slightly more advanced stage (67 g.w. or Carnegie stages 1920), but still before the formation of the cortical plate, the PPL contains numerous GABA+ (Zecevic and Milosevic, 1997) and GAD65/67+ (Meyer et al., 2000
) cells. To characterize further these cells, and to look for their possible origin and migratory routes, we performed in situ hybridization and immunohistochemistry, using probes and antibodies to ventral transcription factors DLX2/DLL and NKX2.1 along with antibodies to the neuronal cell markers.
First we tested the hypothesis that GABA+ interneurons in the embryonic PPL originate from the GE, as has been shown initially in rodents. Both NKX2.1 and DLX proteins were widely distributed through the GE and dorsal telencephalon (Fig. 2A,B). In the cortex, double labeled NKX2.1/GABA and DLX2/GABA cells were observed in the PPL (Fig. 2C,D
). They were horizontally oriented and parallel to the pia. It was noted that DLX2+ cells were predominantly present in the lower part of the PPL (Fig. 2D
), where the pioneer neurons were described (Meyer et al., 2000
). These neurons will reside in the subplate layer once the emerging cortical plate divides the preplate.
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In order to study whether some forebrain interneurons originate in the cortical VZ at the pre-cortical plate stage, we studied in more detail the expression of ventral transcription factors in human embryos.
In the rostral telencephalon, a strong expression of NKX2.1 was observed in the VZ lining the lateral ventricle, continuously from the GE to the cortical VZ (Figs 2A and 5A
). These VZ cells were not co-labeled with either GABA or MAP2 and probably represent immature ventricular cells (Fig. 5AC
). Similar densely packed, radial cells were present in the caudal GE (Fig. 5F
). In the caudal cortex less densely packed NKX2.1, DLX2 and GABA immunopositive cells formed columns in the cortical and hippocampal VZ that alternated with patches without immuno-reactivity (Fig. 2A,B
; Fig. 5D,E,GI
). Some of these cells reached the PPL and acquire neuronal fate as shown by their double labeling with MAP2 (Fig. 5D,E
).
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Does a Subpopulation of CajalRetzius Cells Originate in the GE?
In order to study whether some CajalRetzius cells originate in the GE, co-localization analysis was done with Reelin, a marker of CajalRetzius cells, and ventral transcription factors, NKX2.1 and DLX. In this study we considered Reelin+ cells situated under the pia and above the layer of interneurons to be CajalRetzius cells (Fig. 2E,F). During the preplate period, Reelin+ cells were numerous in the olfactory bulb and rostral cortex (Fig. 6A,B
). The DLX2+ and NKX2.1+ cells also populated both regions (Fig. 6B
), but these ventral telencephalic transcription factors were not expressed by Reelin+ cells. In contrast, in the caudal cortex, some of the Reelin+ cells, in the lower part of the preplate, expressed DLX2 (Fig. 6C
). Additionally, the double-labeled Reelin/DLX2 cells were found in the mantle zone of the caudal GE (Fig. 6D
). Reelin+ cells were also observed in the band that connects the GE to the caudal cortex (Fig. 2F
). These results suggest a region-dependent origin of Reelin+ CajalRetzius cells rostrally located cells presumably originated from the local cortical VZ, while a small population of caudally observed cells probably came from the GE, most likely the LGE, as we never observed Reelin/NKX2.1+ cells.
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Contribution of the Subpial Granular Layer to the Cell Population of Layer I
At 11 g.w., layer I became more complex since at this time the subpial granular layer (SGL) starts emerging on the ventral brain surface (Fig. 7B,C). In sections immunolabeled with calretinin, the first cells that were forming the SGL could be observed to spread from the olfactory region to the nearby ventral cortex. After 13 g.w., the SGL covered the entire cortical surface of the forebrain. In accord with previous studies, the SGL consisted of small GABAergic cells and large Reelin+ CajalRetzius cells (Fig. 7D
) (Meyer and Goffinet, 1998
; Meyer and Wahle, 1999
; Zecevic and Rakic, 2001
).
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Cortical Interneurons at Midgestation
At midgestation (1722 g.w.), the in situ signal for Dlx2 and Nkx2.1 mRNAs was observed in the GE, cortical/hippocampal VZ and SVZ, and developing cortical layers (Fig. 4). A thin line of the Dlx2 and Nkx2.1 mRNA signal in the cortical VZ, with uneven border towards the surrounding tissue, is consistent with the presence of these mRNAs in the cortical VZ cells and the radial migration of these cells towards the overlying cortex (Fig. 4A,D
). A strong Dlx2.1 and Nkx2.1 mRNAs signal connected the GE and the olfactory region (Fig. 4B,C
).
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A large rostral SVZ represents an additional source of cortical interneurons at midgestation (Fig. 8). Numerous vertical cell bands spread from the SVZ towards the overlying cortical plate. These cells, labeled by interneuron markers (CalR, GABA), seem to be migrating in continuous chains along cell bands. In the upper part of the SVZ, cells were aligned along fiber tracts that form a grid-like structure, crossing each others trajectory at right angles. The majority of these cells were also interneurons (Fig. 8E,F
). CalR and GABA+ cells had the morphology of radially or tangentially migrating neurons, with larger leading and thinner trailing processes. Similar to the striato-cortical junction in embryonic stages, adjacent immunolabeled cells were often oriented in opposite directions, either towards the cortical plate or cortical VZ, if radially positioned. If tangentially positioned, the cells were oriented either medially or laterally (Fig. 8E,F
).
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Discussion |
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Embryonic Sources of Layer I Interneurons
A subset of layer I neurons of the human cerebral cortex express NKX and DLX families of transcription factors that are characteristic for the GE. In situ studies corroborated this finding. At the same time, NKX2.1 and DLX expressing cells could be labeled with known markers of cortical interneurons (GABA, CalR or CB). This is similar to what has been reported for rodents (De Carlos et al., 1996; Anderson et al., 1997a
,b
, 2001
; Tamamaki et al., 1997
; Pearlman et al., 1998
; Chapouton et al., 1999
; Lavdas et al., 1999
; Marin and Rubenstein, 2001
), implying that the GE origin of cortical interneurons is well conserved during evolution. However, in the early embryonic stages, before the cortical plate develops, a sub-population of interneurons that express ventral transcription factors (NKX2.1 and DLX2) was observed to be radially oriented in the cortical wall. One explanation of this result is that DLX2 and NKX2.1 cells migrate first tangentially from the GE to the cortical VZ, and then radially through the cortical wall. This has been described in rodents (De Carlos et al., 1996
; Anderson et al., 2001
). However, retroviral labeling of VZ/SVZ cells in slice preparation of the fetal human forebrain show that these cells divide several times before starting radial migration to their final cortical destination, arguing for their cortical origin in humans (Letinic et al., 2002
). In support of this finding, we observed that mRNAs signal and immunolabeling of ventral transcription factors, spread dorsally, to embryonic cortical areas. At the same time, tangentially oriented NKX2.1 and DLX2+ cells were lacking in the embryonic proliferative zone of the forebrain. Taken together, these results suggest that a subpopulation of NKX2.1 and DLX2+ cells present in the cortex, were not coming from the GE. Rather, a more likely possibility is that ventral transcription factors expand dorsally in human brains, labeling also regions of the cortical VZ. Thus, in human brain, ventral transcription factors, DLX and NKX2.1, may not be specific only for GE derived cells. This conclusion is supported both by our in situ results, and by the recent study of human fetal organotypic slice cultures (Letinic et al., 2002
). These authors observed that in human brain only one-third of Dlx1,2-expressing cortical inter-neurons have GE origin, whereas two-thirds have neocortical origin and migrate radially to the overlying cortical plate. This predominance of radial migration over tangential is reflected in the prominent radial organization of the human cerebral cortex during mid-gestation before it become obscured by formation of layers and elaboration of connectivity (McKinstry et al., 2002
). The constant migration of later born neurons from the VZ/SVZ towards the cerebral cortex is reflected in the size of the subplate layer, which reaches its peak in the second half of gestation in human brain (Kostovic et al., 2002
).
Thus, in contrast to rodents, the much larger human brain has additional sources of cortical interneurons that include cortical VZ/SVZ and later on, the SGL.
Bi-directional Neuronal Migration in the Telencephalon
In addition to radial migration towards the pia, as typically observed in the cortical wall, and transverse migration from GE to the neocortex, many cells were heading in the opposite direction. Thus, a possibility that some cortical interneurons, originating from GE, reach preplate layer by tangential migration, and subsequently descend into the cortical wall migrating radially towards the VZ, should also be considered. This type of migration has been observed in live preparation of mouse forebrain by multiphoton microscopy (Ang et al., 2003). This direction of migration would be an additional explanation for the radially oriented DLX2, NKX2.1 or GABA+ cells observed in the embryonic cerebral wall. Thus, both interneurons coming from the cortical VZ, and a subpopulation of cells descending from the layer I, might be radially oriented in the cortical wall. Furthermore, at midgestation, in the subventricular and the intermediate zone, numerous cortical interneurons had their leading processes directed towards the cortical VZ. Similar to this, in the GE, some cells were directed towards the GE-VZ (Fig. 2J
for example). This observation, based only on morphology of cells in human fetal brain, recently was well documented in rodent brain slices and named ventricle-directed migration (Nadarajah et al., 2002
). The suggestion that the VZ is supplying specific layer information to interneurons, similar to information that pyramidal neurons obtain from the cortical VZ, is worth further investigation (Nadarajah et al., 2002
).
A similar phenomenon was present in the striato-cortical junction, where some GABA and CalR interneurons had their leading processes directed towards the GE, as if migrating from the cortex to the GE. Numerous neuronal fibers (calretinin, calbindin, neurofilament proteins-antibodies SMI31 and SMI32) or non-neuronal processes (vimentin, GFAP) were also crossing through the same striato-cortical junction from the early embryonic stages, possibly participating in migration through the junction (Zecevic et al., 1999). Our observation is consistent with the report on embryonic rat slice culture that showed the inward migration into the developing striatum (Hamasaki et al., 2001
).
However, the possibility that cells go forward and then retract for some steps before going forward again, observed by time lapse microscopy for glial cells in organotypic slice cultures (Kakita and Goldman, 1999), cannot be eliminated in our study on frozen sections of human fetal brain.
The Subpial Granular Layer and the Subpopulation of CajalRetzius Cells Contain Ventral Transcription Factors
A transient subpial granular layer (SGL), described first in primates (Brun, 1965; Gadisseux et al., 1992
; Meyer and Goffinet, 1998
; Meyer and Wahle, 1999
; Zecevic and Rakic, 2001
) contains granular GABAergic interneurons and CajalRetzius cells. SGL cells originate from the SVZ close to the olfactory bulb, migrate to the brain surface and give rise to subpial granular cells (Gadissaux et al., 1992; Meyer et al., 1998
; Zecevic and Rakic, 2001
). We have now established that SGL cells were coming from the olfactory region, and that the majority of them express DLX. Either the Dlx cells first migrated from the GE to the olfactory region, or this transcription factor was expressed there from the beginning, since both DLX and NKX2.1+ cells were present in the olfactory region from embryonic stages. In addition, at midgestation, the mRNA signals for the two transcription factors were expressed as a continuous band between the GE and the olfactory region, stressing their connection. At the time when the subpial granular layer starts forming, these cells could spread over the forebrain surface as part of this layer.
The SGL disappeared by 2729 g.w., probably by inward migration of its cells, as was described in the monkey (Zecevic and Rakic, 2001). Rare TUNEL+ cells in this layer show that apoptosis cannot be sufficient for the observed quick removal of this layer (Spreafico et al., 1999
; Rakic and Zecevic, 2000
).
The existence of several subpopulations of CajalRetzius cells indicated on the basis of different antigen expression (Lavdas et al., 1999; Meyer et al., 2000
, 2002
; Zecevic et al., 1999
; Zecevic and Rakic, 2001
), was confirmed in this study by their expression of different transcription factors. Region specific transcription factors can provide the information about the site of origin for different cell types later on, after the cell migrated to distant regions. In the case of Reelin+ CajalRetzius cells, the presence of DLX in subpopulation of these cells speaks in favor that this subpopulation has an LGE origin. Furthermore, bipolar Reelin+ neurons with migratory morphologies were present in the caudal GE of embryonic brains, whereas a stream of Reelin+ cells was observed in continuum from the GE to the neocortex and ventral telencephalon. At the same time the observed lack of radially migrating Reelin+ cells in the cortical wall has been suggested to be due to the fact that CajalRetzius cells express Reelin only after migrating to their position under the pia (Meyer and Wahle, 1999
). However, present results show that migrating cells in the GE can express Reelin. This is consistent with the view that a subpopulation of CajalRetzius cells, traditionally believed to be of cortical origin, could have a subcortical origin from the GE. Recently, similar conclusions have been reached in monkey (Zecevic and Rakic, 2001
) and human (Meyer et al., 2002
) developing forebrain.
The lack of NKX2.1 expression in CajalRetzius cells observed in this study is consistent with the results in rat, where genetically labeled cells transplanted in the MGE migrated to the MZ, but did not express Reelin (Wichterle et al., 2001). Another transcription factor characteristic for MGE, Lhx6, is expressed in some CajalRetzius cells (Lavdas et al., 1999
). At the same time, the expression of Tbr1 in many CajalRetzius cells argues that a larger subpopulation of these cells comes from the cortical ventricular zone (Hevner et al., 2001
). As was discussed above, differences between human and other mammals are likely to exist. In primates the GE might have a larger repertoire of different cell types compared with rodents. Supporting evidence is that, in humans, the GE also contributes neurons to the thalamic nuclei (Sidman and Rakic, 1973
; Letinic and Kostovic, 1997
; Letinic and Rakic, 2001
), and oligodendrocyte progenitors to the forebrain (Ulfig et al., 2002
; Rakic and Zecevic, 2003
).
In summary, the prolonged genesis and multiple sites of origin of cortical interneurons and CajalRetzius cells in the human brain may have important clinical implications. In preterm infants intracerebral hemorrhage in the GE or the periventricular leukomalacia in the near-by subventricular zone (Volpe, 2001; Back et al., 2001
), can destroy a large number of interneurons and oligodendrocytes destined for the cerebral cortex. Depletion of cells in this region during development might have serious consequences, as both cortical interneurons and CajalRetzius cells are implicated in schizophrenia (Benes et al., 1991
; Akbarian et al., 1995
; Impagnatiello et al., 1998
; Lewis, 2000
) and bipolar disorder (Knable, 1999
). The GE is also the site where oligoprogenitors originate (Ulfig et al., 2002
; Rakic and Zecevic, 2003
), and where thalamo-cortical and corticofugal fibers meet and influence each others target finding (Molnar and Blackemore, 1995; Metin and Godement, 1996
; Ulfig et al., 2000
). Thus, it is not surprising that in preterm infants lesions in this region result in some common birth defects (Larroche, 1964
; Gadisseux et al., 1992
; Volpe, 2001
; Back et al., 2001
; Ulfig, 2001
).
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Notes |
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Corresponding author: Dr Nada Zecevic, Department of Neuroscience, University of Connecticut School of Medicine, Farmington, CT 06030, USA. Email: nzecevic{at}neuron.uchc.edu.
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References |
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