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First published online 20 March 2008
doi: 10.1242/dev.014977

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Neural stem cells: balancing self-renewal with differentiation

Howard Hughes Medical Institute, Institute of Neuroscience, Institute of Molecular Biology, University of Oregon, Eugene, OR, USA.

View larger version (25K): [in this window] [in a new window]   Fig. 1. Neural stem cell formation and neuronal differentiation. (A) Drosophila neurogenesis. Neuroectodermal cells (NE; yellow, the apical surface is uppermost) give rise to neuroblasts (NBs; green) by delamination, and each NB divides in a stem cell mode to bud off a chain of ganglion mother cells (GMCs; orange) from its basal surface. GMCs are intermediate precursors that typically generate two postmitotic neurons (n; red). Larval NBs are closely associated with glia (blue). Thoracic and brain NBs become mitotically quiescent in late embryos and resume proliferation during larval stages. Approximate cell cycle times or quiescence times are given in hours (h). epi, embryonic epidermis. (B) Mammalian embryonic cortical neurogenesis. Initially the cortex has only neuroepithelial cells (NE; yellow, the apical surface is uppermost), which mature into radial glia (RG; green). Radial glia and neuroectodermal cells generate basal progenitors (BP; orange), which are intermediate progenitors that generate a limited number of neurons (n; red). NE and RG can also generate neurons. VZ, ventricular zone, adjacent to the lumen; SVZ, subventricular zone; MZ, marginal zone.

View larger version (65K): [in this window] [in a new window]   Fig. 2. Neural stem cell niche. (A) Drosophila larval neuroblast (NB) niche. (Left) Schematic showing NB/glial contact (light blue bars) and cadherin-rich NB/ganglion mother cell (GMC) contacts (red bars). (Right) Confocal image showing glial membrane staining relative to neuroblast and GMC membranes. Glial membrane was detected with repo-gal4 UAS-cd8:GFP (blue, or as a single channel in the right-hand image). NB, GMC and neuronal membranes were labeled with Scribbled (red). Image courtesy of Jason Q. Boone (University of Oregon). (B) Mammalian neuroepithelia/radial glia niche. (Left) Neuroepithelial/radial glia cells contact the ventricular fluid at their apical domain (green dots), neighboring cells via cadherin-rich adherens junctions (AJs; red bars), and the basal lamina at their basal domain (dashed lines). Basal progenitors (BP; orange) and neurons (n; red) lack access to apical and basal cues. (Right) E10 mouse neuroepithelial cells showing cadherin enrichment at the subapical AJs (red) and prominin 1 localization to the apical domain (green) that contacts the ventricular fluid [modified and reproduced with permission from Kosodo et al. (Kosodo et al., 2004)].

View larger version (18K): [in this window] [in a new window]   Fig. 3. Neural stem cell polarity. (A) Drosophila neuroblast cell polarity. (Left) Proteins that asymmetrically localize in a dividing NB. Green, apical proteins; red, basal proteins, including those associated with GMC contact site. Lines between proteins indicate physical interactions. Baz binds Par6 and aPKC (not shown). Arrow indicates that Baz is required for Cdc42 localization. T-bar indicates that aPKC excludes Lgl, Numb and Mira from the cortex, and Lgl excludes aPKC. (Right) Schematic of a dividing NB, showing the apical (green) and basal (red) cortical domains; spindle and centrosomes, brown; DNA, yellow. (B) Mammalian neuroepithelial (NE) cell polarity. (Left) Proteins that asymmetrically localize in a dividing NE cell. Green, apical proteins; red, AJ-enriched proteins; blue basolateral proteins. Lines between protein names indicate physical interactions. Par3 binds Par6 and aPKC (not shown). T-bar indicates that aPKC excludes Lgl and Numb from the cortex. (Right) Schematic of a dividing NE (center). Spindle and centrosomes, brown; DNA, yellow. Baz, Bazooka (fly Par3); Insc, Inscuteable; Pins, Partner of Insc; aPKC, Atypical protein kinase C; Lgl, Lethal giant larvae; Pon, Partner of Numb; Mira, Miranda; Pros, Prospero; Brat, Brain tumor; Stau, Staufen; Ecad, E-cadherin; Apc2, Adenomatosis polyposis coli 2; Prom1, prominin 1; cat, -catenin; βcat, β-catenin; LGN (Gpsm2), a homolog of Pins.

View larger version (25K): [in this window] [in a new window]   Fig. 4. Relationship between spindle orientation and sibling cell fate in neural stem cells. (A) Drosophila neuroblasts. Wild-type neuroblasts (left) invariably align their spindle along the apical/basal polarity axis, resulting in apical neuroblast (NB) and basal GMC cell fates. The cell fates that are acquired when the spindle is misoriented (e.g. in aurora A or mud mutants; right) have not been established. Spindle, blue lines; cleavage furrow plane, dotted line; apical domain, green; basal domain, red. (B) Vertebrate neuroepithelial cells. Conclusions from three different studies are shown. AJs, red balls; apical domain, green; basolateral domain, orange. SC, neuroepithelial cell; BP, basal progenitor; N, neuron. Apical is uppermost. (a) In Kosodo et al. (Kosodo et al., 2004), spindle orientation was concluded to regulate sibling cell fates in mouse embryonic neuroepithelial cells: if both siblings receive apical components (green), they both self-renew as progenitors (SCs; left); but if one cell lacks apical components, it differentiates into a neuron (N, middle and right). This type of asymmetric division can occur when the spindle is positioned in a near-planar orientation (middle) or in an apical/basal orientation (right). Thus, spindle orientation alone is insufficient to predict cell fate outcome. (b) Konno et al. (Konno et al., 2008) concluded that spindle orientation regulates sibling cell fates in mouse embryonic neuroepithelial cells: only siblings that inherit both apical and basal components will self-renew as progenitors (left); cells containing only apical domain become basal progenitors (BP; middle), whereas cells containing only the basal process become neurons (N; middle and right). (c) Morin et al. (Morin et al., 2007) concluded that spindle orientation does not affect sibling cell fates in the chick spinal cord. Normally, all divisions during early neurogenesis have a planar spindle orientation and form two progenitors (left). However, when the basolateral protein LGN (Gpsm2) was reduced by siRNA, the spindle could align with the apical/basal axis, yet both siblings still maintained progenitor identity by molecular marker expression (right), although the non-apical sibling was displaced out of the ventricular zone. Apical membrane and junction markers were not used in this study and thus are not shown.

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