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 ␣6␤1 integrin, syndecan-1, and lutheran, and in vivo blocking of ␤1 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.

SummaryThe expression of adhesion molecules by stem cells within their niches is well described, but what is their function? A conventional view is that these adhesion molecules simply retain stem cells in the niche and thereby maintain its architecture and shape. Here, we review recent literature showing that this is but one of their roles, and that they have essential functions in all aspects of the stem cellniche interaction -retention, division and exit. We also highlight from this literature evidence supporting a simple model whereby the regulation of centrosome positioning and spindle angle is regulated by both cadherins and integrins, and the differential activity of these two adhesion molecules enables the fundamental stem cell property of switching between asymmetrical and symmetrical divisions.Key words: Cadherin, Integrin, Adherens junction, Basal lamina, Centrosome, Stem cell niche Journal of Cell Sciencedirectly for follicle stem cells in the Drosophila ovary, where cells that lack the -integrin subunit PS were frequently mislocalised into the centre of the gonad, away from their normal location on the basal lamina at the edge (O'Reilly et al., 2008) (Fig. 1D). Interestingly, these stem cells also produce laminins, and laminins constitute one of the integrin ligands in the underlying basal lamina. This, therefore, provides an example of stem cells generating the signals required for their own maintenance within the niche.In adult mammalian niches, the role for adhesion molecules in retaining the correct position of stem cells remains unproven. In the bone marrow niche of haematopoietic stem cells (HSCs), a population of HSCs is located adjacent to the endosteum, the cell layer on the bone surface (Kiel et al., 2005;Zhang et al., 2003). It has been proposed that the HSCs are anchored to a subpopulation of osteoblasts at this site by N-cadherin, with these osteoblasts providing a niche environment (Zhang et al., 2003) -a situation analogous to that in Drosophila stromal gonadal niches. However, studies that used the signalling lymphocyte activating molecule (SLAM) family of lymphocyte receptors as markers of HSCs revealed that only a minority of HSCs is found adjacent to the endosteum; by contrast, the majority was found to be associated with the sinusoidal endothelial cells within the bone (Kiel et al., 2005). Furthermore, mice with greatly reduced numbers of osteoblasts have no alterations in HSC numbers (Kiel et al., 2007), and the conditional deletion of N-cadherin from HSCs has no effect on haematopoiesis (Kiel et al., 2009). Together, these observations cast doubt on the concept of an N-cadherin-dependent osteoblastic niche as being required for haematopoiesis. With respect to integrins, it has been reported that epithelial stem cells in several tissues, including the skin and brain, express high levels of 6 and/or 1 integrins (which heterodimerise to generate a laminin receptor) (Hall et al., 2006; Jones and Watt, 1993). Equally, laminins that contact the stem cells are present in the under...

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.

Basal lamina is present in many stem cell niches, but we still have a poor understanding of the role of these and other extracellular matrix components. Here we review current knowledge regarding extracellular matrix expression and function in the neural stem cell niche, focusing on the subependymal zone of the adult CNS. An increasing complexity of extracellular matrix molecules has been described, and a number of receptors expressed on the stem cells identified. Experiments perturbing the niche using genetics or cytotoxic ablation of the rapidly dividing precursors, or using explant culture models to examine specific growth factors, have been influential in showing how changes in these extracellular matrix receptors regulate neural stem cell behaviour. However the role of changes in the matrix itself remains to be determined. The answers will be important, as they will point to the molecules required to engineer niches ex-vivo so as to provide tools for regenerative neuroscience.

The subependymal zone (SEZ) of the lateral ventricles of the adult mouse brain hosts neurogenesis from a neural stem cell population with the morphology of astrocytes (termed type-B cells). Tenascin-C is a large extracellular matrix glycoprotein present in the SEZ that has been shown to regulate the development of embryonic neural stem cells and the proliferation and migration of early postnatal neural precursors. Here we show that tenascin-C is produced by type-B cells and forms a layer between SEZ and the adjacent striatum. Tenascin-C deficiency resulted in minor structural differences in and around the SEZ. However, the numbers of neural stem cells and their progeny remained unaffected, as did their regeneration after depletion of mitotic cells using the antimitotic drug cytosine-␤-Darabinofuranoside. Our results reveal a remarkable ability of the adult neural stem cell niche to retain proper function even after the removal of major extracellular matrix molecules.

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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.

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.