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1.  Disc1 Variation Leads to Specific Alterations in Adult Neurogenesis 
PLoS ONE  2014;9(10):e108088.
Disrupted in schizophrenia 1 (DISC1) is a risk factor for a spectrum of neuropsychiatric illnesses including schizophrenia, bipolar disorder, and major depressive disorder. Here we use two missense Disc1 mouse mutants, described previously with distinct behavioural phenotypes, to demonstrate that Disc1 variation exerts differing effects on the formation of newly generated neurons in the adult hippocampus. Disc1 mice carrying a homozygous Q31L mutation, and displaying depressive-like phenotypes, have fewer proliferating cells while Disc1 mice with a homozygous L100P mutation that induces schizophrenia-like phenotypes, show changes in the generation, placement and maturation of newly generated neurons in the hippocampal dentate gyrus. Our results demonstrate Disc1 allele specific effects in the adult hippocampus, and suggest that the divergence in behavioural phenotypes may in part stem from changes in specific cell populations in the brain.
PMCID: PMC4182707  PMID: 25272038
2.  The late response of rat subependymal zone stem and progenitor cells to stroke is restricted to directly affected areas of their niche☆ 
Experimental Neurology  2013;248(100):387-397.
Ischaemia leads to increased proliferation of progenitors in the subependymal zone (SEZ) neurogenic niche of the adult brain and to generation and migration of newborn neurons. Here we investigated the spatiotemporal characteristics of the mitotic activity of adult neural stem and progenitor cells in the SEZ during the sub-acute and chronic post-ischaemic phases. Ischaemia was induced by performing a 1 h unilateral middle cerebral artery occlusion (MCAO) and tissue was collected 4/5 weeks and 1 year after the insult. Neural stem cells (NSCs) responded differently from their downstream progenitors to MCAO, with NSCs being activated only transiently whilst progenitors remain activated even at 1 year post-injury. Importantly, mitotic activation was observed only in the affected areas of the niche and specifically in the dorsal half of the SEZ. Analysis of the topography of mitoses, in relation to the anatomy of the lesion and to the position of ependymal cells and blood vessels, suggested an interplay between lesion-derived recruiting signals and the local signals that normally control proliferation in the chronic post-ischaemic phase.
•Neural stem cells respond transiently to ischaemia.•Progenitors respond chronically to ischaemia.•Neural stem/progenitor cells of the subependymal zone respond only in areas of damage to the niche.•Ischaemia affects the cytoarchitecture of mitoses in the ageing niche.•Density of microglia is decreased in the ageing niche.
PMCID: PMC3782662  PMID: 23830949
Neurogenesis; Neural stem cells; Progenitors; Subependymal zone/subventricular zone; Stroke; Ischaemia; Proliferation
3.  The Number of Stem Cells in the Subependymal Zone of the Adult Rodent Brain is Correlated with the Number of Ependymal Cells and Not with the Volume of the Niche 
Stem Cells and Development  2011;21(7):1090-1096.
The mammalian subependymal zone (SEZ; often called subventricular) situated at the lateral walls of the lateral ventricles of the brain contains a pool of relatively quiescent adult neural stem cells whose neurogenic activity persists throughout life. These stem cells are positioned in close proximity both to the ependymal cells that provide the cerebrospinal fluid interface and to the blood vessel endothelial cells, but the relative contribution of these 2 cell types to stem cell regulation remains undetermined. Here, we address this question by analyzing a naturally occurring example of volumetric scaling of the SEZ in a comparison of the mouse SEZ with the larger rat SEZ. Our analysis reveals that the number of stem cells in the SEZ niche is correlated with the number of ependymal cells rather than with the volume, thereby indicating the importance of ependymal-derived factors in the formation and function of the SEZ. The elucidation of the factors generated by ependymal cells that regulate stem cell numbers within the SEZ is, therefore, of importance for stem cell biology and regenerative neuroscience.
PMCID: PMC3328758  PMID: 21762017
4.  Niche derived oligodendrocyte progenitors: a source of rejuvenation or complementation for local oligodendrogenesis? 
PMCID: PMC3804763  PMID: 24155691
oligodendrocyte precursor cell (OPC); Myelination; subventricular zone (SVZ); subependymal zone; glia cell; stem cell; CNS
5.  Dual Function of Sox1 in Telencephalic Progenitor Cells 
Developmental biology  2007;310(1):85-98.
The transcription factor, Sox1 has been implicated in the maintenance of neural progenitor cell status, but accumulating evidence suggests that this is only part of its function. This study examined the role of Sox1 expression in proliferation, lineage commitment, and differentiation by telencephalic neural progenitor cells in vitro and in vivo, and further clarified the pattern of Sox1 expression in postnatal and adult mouse brain. Telencephalic neural progenitor cells isolated from Sox1 null embryos formed neurospheres normally, but were specifically deficient in neuronal differentiation. Conversely, overexpression of Sox1 in the embryonic telencephalon in vivo both expanded the progenitor pool and biased neural progenitor cells towards neuronal lineage commitment. Sox1 mRNA and protein were found to be persistently expressed in the postnatal and adult brain in both differentiated and neurogenic regions. Importantly, in differentiated regions Sox1 co-labeled only with neuronal markers. These observations, coupled with previous studies, suggest that Sox1 expression by early embryonic progenitor cells initially helps to maintain the cells in cell cycle, but that continued expression subsequently promotes neuronal lineage commitment.
PMCID: PMC3437622  PMID: 17719572
Sox1; neural progenitor cells; neural stem cells; neurogenesis; differentiation
6.  Quiescence and Activation of Stem and Precursor Cell Populations in the Subependymal Zone of the Mammalian Brain Are Associated with Distinct Cellular and Extracellular Matrix Signals 
The Journal of Neuroscience  2010;30(29):9771-9781.
The subependymal zone (SEZ) of the lateral ventricles is one of the areas of the adult brain where new neurons are continuously generated from neural stem cells (NSCs), via rapidly dividing precursors. This neurogenic niche is a complex cellular and extracellular microenvironment, highly vascularized compared to non-neurogenic periventricular areas, within which NSCs and precursors exhibit distinct behavior. Here, we investigate the possible mechanisms by which extracellular matrix molecules and their receptors might regulate this differential behavior. We show that NSCs and precursors proceed through mitosis in the same domains within the SEZ of adult male mice—albeit with NSCs nearer ependymal cells—and that distance from the ventricle is a stronger limiting factor for neurogenic activity than distance from blood vessels. Furthermore, we show that NSCs and precursors are embedded in a laminin-rich extracellular matrix, to which they can both contribute. Importantly, they express differential levels of extracellular matrix receptors, with NSCs expressing low levels of α6β1 integrin, syndecan-1, and lutheran, and in vivo blocking of β1 integrin selectively induced the proliferation and ectopic migration of precursors. Finally, when NSCs are activated to reconstitute the niche after depletion of precursors, expression of laminin receptors is upregulated. These results indicate that the distinct behavior of adult NSCs and precursors is not necessarily regulated via exposure to differential extracellular signals, but rather via intrinsic regulation of their interaction with their microenvironment.
PMCID: PMC3842479  PMID: 20660259
7.  The subependymal zone neurogenic niche: a beating heart in the centre of the brain 
Brain  2009;132(11):2909-2921.
The mammalian brain is a remarkably complex organ comprising millions of neurons, glia and various other cell types. Its impressive cytoarchitecture led to the long standing belief that it is a structurally static organ and thus very sensitive to injury. However, an area of striking structural flexibility has been recently described at the centre of the brain. It is the subependymal zone of the lateral wall of the lateral ventricles. The subependymal zone—like a beating heart—continuously sends new cells to different areas of the brain: neurons to the olfactory bulbs and glial cells to the cortex and the corpus callosum. Interestingly, the generation and flow of cells changes in response to signals from anatomically remote areas of the brain or even from the external environment of the organism, therefore indicating that subependymal neurogenesis—as a system—is integrated in the overall homeostatic function of the brain. In this review, it will be attempted to describe the fundamental structural and functional characteristics of the subependymal neurogenic niche and to summarize the available evidence regarding its plasticity. Special focus is given on issues such as whether adult neural stem cells are activated after neurodegeneration, whether defects in neurogenesis contribute to neuropathological conditions and whether monitoring changes in neurogenic activity can have a diagnostic value.
PMCID: PMC2768664  PMID: 19773354
adult neural stem cells; neurodegeneration; neurogenesis; subependymal zone; subventricular zone
8.  Neuronal Migration and Ventral Subtype Identity in the Telencephalon Depend on SOX1 
PLoS Biology  2005;3(6):e186.
Little is known about the molecular mechanisms and intrinsic factors that are responsible for the emergence of neuronal subtype identity. Several transcription factors that are expressed mainly in precursors of the ventral telencephalon have been shown to control neuronal specification, but it has been unclear whether subtype identity is also specified in these precursors, or if this happens in postmitotic neurons, and whether it involves the same or different factors. SOX1, an HMG box transcription factor, is expressed widely in neural precursors along with the two other SOXB1 subfamily members, SOX2 and SOX3, and all three have been implicated in neurogenesis. SOX1 is also uniquely expressed at a high level in the majority of telencephalic neurons that constitute the ventral striatum (VS). These neurons are missing in Sox1-null mutant mice. In the present study, we have addressed the requirement for SOX1 at a cellular level, revealing both the nature and timing of the defect. By generating a novel Sox1-null allele expressing β-galactosidase, we found that the VS precursors and their early neuronal differentiation are unaffected in the absence of SOX1, but the prospective neurons fail to migrate to their appropriate position. Furthermore, the migration of non-Sox1-expressing VS neurons (such as those expressing Pax6) was also affected in the absence of SOX1, suggesting that Sox1-expressing neurons play a role in structuring the area of the VS. To test whether SOX1 is required in postmitotic cells for the emergence of VS neuronal identity, we generated mice in which Sox1 expression was directed to all ventral telencephalic precursors, but to only a very few VS neurons. These mice again lacked most of the VS, indicating that SOX1 expression in precursors is not sufficient for VS development. Conversely, the few neurons in which Sox1 expression was maintained were able to migrate to the VS. In conclusion, Sox1 expression in precursors is not sufficient for VS neuronal identity and migration, but this is accomplished in postmitotic cells, which require the continued presence of SOX1. Our data also suggest that other SOXB1 members showing expression in specific neuronal populations are likely to play continuous roles from the establishment of precursors to their final differentiation.
The mechanisms whereby neurons establish their final identity are largely unknown. This study shows that the transcription factor SOX1 plays an important part in this process.
PMCID: PMC1110909  PMID: 15882093

Results 1-8 (8)