Telencephalic Subventricular Zone Research Articles

Temporally Distinct Roles for the Zinc Finger Transcription Factor Sp8 in the Generation and Migration of Dorsal Lateral Ganglionic Eminence (dLGE)-Derived Neuronal Subtypes in the Mouse.

Progenitors in the dorsal lateral ganglionic eminence (dLGE) are known to give rise to olfactory bulb (OB) interneurons and intercalated cells (ITCs) of the amygdala. The dLGE enriched transcription factor Sp8 is required for the normal generation of ITCs as well as OB interneurons, particularly the calretinin (CR)-expressing subtype. In this study, we used a genetic gain-of-function approach in mice to examine the roles Sp8 plays in controlling the development of dLGE-derived neuronal subtypes. Misexpression of Sp8 throughout the ventral telencephalic subventricular zone (SVZ) from early embryonic stages, led to an increased generation of ITCs which was dependent on Tshz1 gene dosage. Additionally, Sp8 misexpression impaired rostral migration of OB interneurons with clusters of CR interneurons seen in the SVZ along with decreased differentiation of calbindin OB interneurons. Sp8 misexpression throughout the ventral telencephalon also reduced ventral LGE neuronal subtypes including striatal projection neurons. Delaying Sp8 misexpression until E14-15 rescued the striatal and amygdala phenotypes but only partially rescued OB interneuron reductions, consistent with an early window of striatal and amygdala neurogenesis and ongoing OB interneuron generation at this late stage. Our results demonstrate critical roles for the timing and neuronal cell-type specificity of Sp8 expression in mouse LGE neurogenesis.

Perspectives of TRPV1 Function on the Neurogenesis and Neural Plasticity.

The development of new strategies to renew and repair neuronal networks using neural plasticity induced by stem cell graft could enable new therapies to cure diseases that were considered lethal until now. In adequate microenvironment a neuronal progenitor must receive molecular signal of a specific cellular context to determine fate, differentiation, and location. TRPV1, a nonselective calcium channel, is expressed in neurogenic regions of the brain like the subgranular zone of the hippocampal dentate gyrus and the telencephalic subventricular zone, being valuable for neural differentiation and neural plasticity. Current data show that TRPV1 is involved in several neuronal functions as cytoskeleton dynamics, cell migration, survival, and regeneration of injured neurons, incorporating several stimuli in neurogenesis and network integration. The function of TRPV1 in the brain is under intensive investigation, due to multiple places where it has been detected and its sensitivity for different chemical and physical agonists, and a new role of TRPV1 in brain function is now emerging as a molecular tool for survival and control of neural stem cells.

Extracerebellar progenitors grafted to the neurogenic milieu of the postnatal rat cerebellum adapt to the host environment but fail to acquire cerebellar identities

Stem or progenitor cells acquire specific regional identities during early ontogenesis. Nonetheless, there is evidence that cells heterotopically transplanted to neurogenic regions of the developing or mature central nervous system may switch their fate to adopt host-specific phenotypes. Here, we isolated progenitor cells from different germinative sites along the neuraxis where GABAergic interneurons are produced (telencephalic subventricular zone, medial ganglionic eminence, ventral mesencephalon and dorsal spinal cord), and grafted them to the prospective white matter of the postnatal rat cerebellum, at the time when local interneurons are generated. The phenotype acquired by transplanted cells was assessed by different criteria, including expression of region-specific transcription factors, acquisition of morphological and neurochemical traits, and integration in the cerebellar cytoarchitecture. Regardless of their origin, all the different types of donor cells engrafted in the cerebellar parenchyma and developed mature neurons that shared some morphological and neurochemical features with local inhibitory interneurons, particularly in the deep nuclei. Nevertheless, transplanted cells failed to activate cerebellar-specific regulatory genes. In addition, their major structural features, the expression profiles of type-specific markers and the laminar placement in the recipient cortex did not match those of endogenous interneurons generated during the same developmental period. Therefore, although exogenous cells are influenced by the cerebellar milieu and show remarkable capabilities for adapting to the foreign environment, they essentially fail to switch their fate, integrate in the host neurogenic mechanisms and adopt clear-cut cerebellar identities.

Telencephalon enlargement by the convergent evolution of expanded subventricular zones

Some mammals and birds independently evolved an enlarged telencephalon. They appear to have done so, at least in part, by developing a thick telencephalic subventricular zone (SVZ). We suggest that this correlation between telencephalic enlargement and SVZ expansion is due to a mechanical constraint acting on the proliferative ventricular zone (VZ). Essentially, we argue that rapid proliferation in the VZ after post-mitotic cells in the overlying mantle zone have begun to form limits the VZ's tangential expandability and forces some proliferating cells to emigrate from the VZ and expand the pool of proliferating cells that comprise the SVZ.

Cellular composition and cytoarchitecture of the rabbit subventricular zone and its extensions in the forebrain

Persistent neurogenic sites, harboring neurogenic progenitor cells, which give rise to neuronal precursors throughout life, occur in different mammals, including humans. The telencephalic subventricular zone (SVZ) is the most active adult neurogenic site. Despite remarkable knowledge of its anatomical and cellular composition in rodents, detailed arrangement of SVZ in other mammals is poorly understood, yet comparative studies suggest that differences might exist. Here, by analyzing the cellular composition/arrangement in the SVZ of postnatal, young, and adult rabbits, we found a remarkably heterogeneous distribution of its chain and glia compartments. Starting from postnatal stages, this heterogeneity leads to a distinction between a ventricular SVZ and an abventricular SVZ, whereby the former contains small chains and isolated neuroblasts and the latter is characterized by large chains and a loose astrocytic meshwork. In addition to analysis of the SVZ proper, attention has been focused on its extensions, called parenchymal chains. Anterior parenchymal chains are compact chains surrounded by axon bundles and frequently establish direct contact with blood vessels. Posterior parenchymal chains are less compact, being squeezed between gray and white matter. In the shift from neonatal to adult rabbit SVZ, chains occur very early, both in the SVZ and within the brain parenchyma. Comparison of these results with the pattern in rodents reveals different types of chains, displaying a variety of relationships with glia or other substrates in vivo, an issue that might be important in understanding differences in the adaptation of persistent germinative layers to different mammalian brain anatomies.

The distribution of expression of doublecortin (DCX) mRNA and protein in the zebra finch brain

Using in situ hybridization, we measured the distribution of expression of doublecortin (DCX), a microtubule-associated protein, in zebra finch adult and nestling (P9–11) brains. In adult brain, DCX mRNA was detected mainly in the mesopallium (M), medial striatum (MSt), septum, Area X, diencephalon, telencephalic subventricular zone (SVZ), and Purkinje cells in the cerebellum. The expression at posthatch day 9 (P9) was heavy in almost the entire telencephalon and showed heavier expression in SVZ and song regions such as the high vocal center (HVC) and the robust nucleus of arcopallium (RA). Outside of the telencephalon at P9, we found distinct label in nucleus ovoidalis (OV), nucleus spiriformis lateralis (SpL), and nucleus subpretectalis (SP) in the midbrain, almost the entire diencephalon including nucleus dorsomedialis posterior thalami (DMP), stratum griseum et fibrosum superficiale (SGF) in optic tectum, and Purkinje cells in cerebellum. Most of the heavily labeled areas by in situ hybridization overlapped with immunohistochemical staining for DCX, indicating that DCX mRNA is probably translated into protein in those regions. No sex difference was found in DCX expression at P9 or in the adult except that Area X was labeled only in the adult male. The intensity of expression in the adult was significantly lower than that at P9, which suggests a particular role for DCX in early song bird brain development. If DCX is predominantly expressed in migrating neurons, as suggested from studies in mammals, the present results offer no evidence for a sex difference in neuronal migration.

Mash1 specifies neurons and oligodendrocytes in the postnatal brain

Progenitors in the telencephalic subventricular zone (SVZ) remain mitotically active throughout life, and produce different cell types at embryonic, postnatal and adult stages. Here we show that Mash1, an important proneural gene in the embryonic telencephalon, is broadly expressed in the postnatal SVZ, in progenitors for both neuronal and oligodendrocyte lineages. Moreover, Mash1 is required at birth for the generation of a large fraction of neuronal and oligodendrocyte precursors from the olfactory bulb. Clonal analysis in culture and transplantation experiments in postnatal brain demonstrate that this phenotype reflects a cell-autonomous function of Mash1 in specification of these two lineages. The conservation of Mash1 function in the postnatal SVZ suggests that the same transcription mechanisms operate throughout life to specify cell fates in this structure, and that the profound changes in the cell types produced reflect changes in the signalling environment of the SVZ.

Identification of Golli and myelin basic proteins in human brain during early development.

The myelin basic protein gene (Mbp) encodes for the major myelin structural proteins and it is included in the Golli-Mbp gene complex. Previously, we observed MBP-like proteins in the human central nervous system (CNS) at developmental stages preceding myelination. In an effort to distinguish between Golli (HOG5 and HOG7) and MBP mRNAs and to determine their spatiotemporal distribution, we performed in situ hybridization using two human Golli specific probes: one corresponding to exon 5a absent from all MBP transcripts, and the other corresponding to exon 5c specific for HOG5. HOG7 transcript was observed first, in 5 gestational week-old embryos, whereas both Golli transcripts were detected at 6-7 weeks gestation in the proliferative zones of the entire CNS. Golli proteins immunoreactivity was observed in microglia and early neurons of the developing telencephalon. During midgestation (17-22 weeks gestation), at the onset of myelination, MBP and Golli mRNAs were observed in the telencephalic subventricular zone and occasionally in the future cerebral cortex. Developmental expression of the human Golli-Mbp indicates that the two Golli proteins have different onset of expression, distribution and possibly function. These results support the hypothesis that at least one of them, HOG7, may be involved in the regulation of early neurogenesis, while both may have additional, still undefined function at the onset of myelination.

Cell cycle length of olfactory bulb neuronal progenitors in the rostral migratory stream.

The anterior portion of the neonatal telencephalic subventricular zone (SVZa) contains proliferating cells that generate an immense number of neurons destined to become the granule and periglomerular cells of the olfactory bulb. In contrast to other immature neurons in the central nervous system, cells arising in the SVZa maintain the ability to divide as they traverse the rostral migratory stream to their final destinations despite expressing an antigenic marker of differentiated neurons (Menezes et al. [1995] Molec. Cell. Neurosci. 6:496-508). Because of their considerable proliferative capacities and unusual mitotic behavior, we decided to determine the cell cycle length of proliferating cells within the SVZa and within the migratory pathway used by SVZa-derived cells. Following the methodology of Nowakowski et al. [1989](J. Neurocytol. 18:311-318), postnatal day 2 rat pups were exposed to 5'-bromo-2'deoxyuridine (BrdU) for increasing periods of time before perfusion. By plotting the percentage of nuclei undergoing DNA synthesis in the SVZa at each time versus the BrdU labeling interval, we determined that approximately 15% of the SVZa population is actively dividing and that these cells have a cycle length of approximately 14 hr, significantly less than the 18.6 hr determined to be the cycle length of dividing cells in more posterior, glia-generating regions of the subventricular zone (Thomaidou et al. [1997] J. Neurosci. 17:1075-1085). The cycle length of cells dividing in the mid portion of the rostral migratory stream, however, is considerably longer: 17.3 hr. This may reflect the need for these cells to coordinate the processes of migration and division. Our studies also suggest that there may be regional differences in the types of descendants produced by the proliferating cells. Retroviral lineage tracing studies showed that those cells that divide within the rostral migratory stream, like proliferating cells within the SVZa, make cells destined for the olfactory bulb. Unlike the progenitors that divide within the SVZa and generate more granule cells than periglomerular cells, the proliferating cells within the migratory pathway generate more periglomerular cells than granule cells. Collectively the proliferating cells of the SVZa and migratory pathway produce a large number of olfactory bulb interneurons. Our work suggests that this may be achieved in part by the relatively rapid divisions of progenitor cells within the SVZa and in part by the ongoing division of migrating cells en route to the olfactory bulb.

Divergent lineages for oligodendrocytes and astrocytes originating in the neonatal forebrain subventricular zone

Although previous studies have revealed that the prenatal rat ventricular zone contains separate progenitor cells for neurons, astrocytes, and oligodendrocytes during the development of the cerebral cortex as early as the beginning of neurogenesis (Luskin et al., 1993; Grove et al., 1993), it is still unclear whether there are bipotential progenitor cells in the neonatal telencephalic subventricular zone which give rise to both astrocytes and oligodendrocytes during the peak of gliogenesis. To investigate this possibility, discrete groups of clonally related cells, generated by infecting progenitor cells of the neonatal subventricular zone with a retroviral lineage tracer, were analyzed ultrastructurally. An intracerebral injection of retrovirus encoding the reporter gene E. coli beta-galactosidase (lacZ) was made into the subventricular zone of newborn rats. Two weeks later their brains were perfused, sectioned, and histochemically reacted with X-Gal to identify at the light microscopic level clones of lacZ-positive cells. The sections were processed for electron microscopy to enable the identity of clonally related cells to be assessed at the ultrastructural level. All of the clones analyzed contained cells of the same phenotype and could be divided into four distinct types: immature cell clones situated in the subependymal zone surrounding the lateral ventricle, oligodendrocytes clones, and white or gray matter astrocyte clones. Not all of the cells in every clone displayed ultrastructural features of a mature cell. Rather, in some glial clones the lacZ-positive cells appeared to be at different stages of differentiation. However, we never encountered clones which contained both macroglial subtypes or clones containing neurons. Although the existence of bipotential progenitor cells cannot be completely dismissed, our results indicate the absence of progenitor cells in vivo in the neonatal subventricular zone which divide and generate astrocytes and oligodendrocytes.

Rate and pattern of migration of lineally-related olfactory bulb interneurons generated postnatally in the subventricular zone of the rat.

A spatially discrete region of the anterior part of the postnatal telencephalic subventricular zone, referred to as the SVZa generates vast numbers of lineally-related neurons destined for the olfactory bulb (Luskin, 1993). The cells originating in the SVZa migrate to the olfactory bulb along a highly restricted pathway which is in a direction orthogonal to the orientation of radial glial fibers. In this study we analysed the number, distribution, orientation and rate of migration of SVZa-derived cells as they approach the olfactory bulb. In order to track the SVZa-derived cells, a retroviral lineage tracer, encoding the reporter gene E. coli beta-galactosidase (lacZ) was injected precisely into the rat SVZa at postnatal day 1 (P1). The lacZ-positive cells were visualized 1, 2 and 3 days later by X-Gal histochemistry in cryostat sections. As the number of SVZa-derived cells in the pathway increased with survival time, their distribution changed systematically. The distribution pattern of lacZ-positive cells by 2 and 3 days postinjection suggested that some of the progeny of infected progenitor cells were undergoing neurogenesis as they proceeded to the olfactory bulb; a large percentage of the lacZ-positive cells were substantially displaced from the SVZa injection site. To investigate whether lacZ-positive cells migrate in a directed fashion, their orientation preference was scored. For the majority of lacZ-positive cells (> 94%), their leading process was directed toward the olfactory bulb, possibly reflecting a response to migratory cues present along the pathway. The estimated average rate of cell migration to the olfactory bulb was 23 mu m/h, which is approximately twice the speed of radially directed neuronal migration from the telencephalic ventricular zone to the cortical plate (O'Rourke et al., 1992). Collectively, these results suggest that SVZa-derived interneurons en route to the olfactory bulb may employ a novel mode of tangential migration.