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.

The dentate gyrus (DG) of the hippocampus has a central role in learning and memory in adult rodents. The DG is generated soon after birth, although new neurons continue to be generated in the DG throughout life. The proneural factors Mash1 (Ascl1) and neurogenin 2 (Ngn2) are expressed during formation of the DG but their role in the development of this structure has not yet been addressed. Here, we show that Ngn2 is essential for the development of the DG. Ngn2 mutant mice have fewer DG progenitors and these cells present defects in neuronal differentiation. By contrast, the DG is normal in Mash1 mutant mice at birth, and loss of both Mash1 and Ngn2 does not aggravate the defect observed in Ngn2 single mutants. These data establish a unique role of Ngn2 in DG neurogenesis during development and raise the possibility that Ngn2 has a similar function in adult neurogenesis.

Neural stem cells (NSCs) reside in specialized niches in the adult mammalian brain, including the subventricular zone and the dentate gyrus, which act to control NSC behavior. Among other cell types within these niches, NSCs are found in close proximity to blood vessels. We carried out an analysis of the interaction between endothelial cells and NSCs, and show that betacellulin (BTC), a member of the EGF family and one of several signaling molecules made by the former, induces NSC proliferation and prevents spontaneous differentiation in culture. When infused into the lateral ventricle, BTC induces expansion of NSCs and neuroblasts, and promotes neurogenesis in the olfactory bulb and dentate gyrus, whereas specific blocking antibodies reduce the number of stem/progenitor cells. BTC-null mice are less able to regenerate neuroblast numbers compared with WT littermates following depletion of proliferating cells using cytosine-β-D-arabinofuranoside. BTC acts via both the EGF receptor, located on NSCs, and ErbB4, located on neuroblasts, with the latter explaining why its effects are distinct from those of EGF itself. Our results suggest that BTC could be a good candidate to aid regenerative therapies. . Two main NSC niches have been described in the adult mouse brain: the subventricular zone (SVZ) and the dentate gyrus (DG) in the hippocampus (1, 2). Located on the lateral wall of the lateral ventricles, the SVZ is composed of different cell populations, including a monolayer of ependymal cells that lines the ventricle, NSCs, transit-amplifying cells, neural progenitors (neuroblasts), astrocytes, and a dense network of blood vessels. NSCs extend a process to the ventricle through the ependymal layer and also to endothelial cells (ECs) in the niche, and therefore maintain contact with both the ventricular space and the blood vessels (3).In the SVZ, which is densely vascularized, neurogenesis is associated with the vasculature and most proliferating cells are found adjacent or very close to blood vessels (4, 5). GFAP + astrocytic stem cells and transit-amplifying progenitor cells are located in the proximity of the capillaries and chains of neuroblasts line the vessels as they migrate along the rostral migratory stream (RMS), although without direct contact (4, 5). Progenitor cells are recruited to the niche vasculature by SDF-1, and their continuing interaction is dependent on α6β1 integrin (5, 6). The functional effect that ECs exert on NSCs can be reproduced in vitro. ECs, but not smooth muscle cells, induce NSC proliferation in coculture experiments, prevent their differentiation, and enhance their neurogenic capacity (7). Both ECs and ependymal cells support NSC self-renewal, at least in part, by secreting pigment epithelium-derived factor (8). However, although these data strongly suggest that blood vessels have an impact on NSCs, niche homeostasis, and neurogenesis, the underlying molecular mechanisms are far from being understood and are likely to involve additional components. Interestingly, stem/progenitor ce...

Little is known of the transcription factors expressed by adult neural progenitors produced in the hippocampal neurogenic niche. Here, we study the expression of the proneural basic helix-loop-helix (bHLH) transcription factor Neurogenin-2 (Ngn2) in the adult hippocampus. We have characterized the pattern of expression of Ngn2 in the adult hippocampus using immunostaining for Ngn2 protein and a Ngn2-green fluorescent protein (GFP) reporter mouse strain. A significant proportion of Ngn2-expressing cells were mitotically active. Ngn2-GFP expression was restricted to the subgranular zone and declined with age. Neuronal markers were used to determine the phenotype of Ngn2-expressing cells. The vast majority of Ngn2-GFP-positive cells expressed the immature neuronal markers, doublecortin (DCX) and polysialic acid-neural cell adhesion molecule (PSA-NCAM). Finally, the pattern of Ngn2 expression was studied following seizure induction. Our data show an increase in neurogenesis, detected in these animals by bromodeoxyuridine (BrdU) and DCX staining that was contemporaneous with a marked increase in Ngn2-GFP-expression. Taken together, our results show that Ngn2-GFP represents a specific marker for neurogenesis and its modulation in the adult hippocampus. Ngn2 transient expression in proliferating neuronal progenitors supports the idea that it plays a significant role in adult neurogenesis.

Nestin-Cre mice express Cre recombinase under control of the rat nestin promoter and central nervous system (CNS) enhancer. While endogenous Nestin is expressed in some other tissues including the pituitary gland, Nestin-Cre mice induce recombination predominantly in the CNS. For this reason, they have been widely used to explore gene function or cell fate in the latter. Pituitary hormonal deficiencies, or hypopituitarism, are associated with a wide range of symptoms and with a significant morbidity. These can have a neural and/or a pituitary origin as the gland's secretions are controlled by the hypothalamus. We report here that Nestin-Cre mice themselves are affected by mild hypopituitarism. Hence, physiological consequences are expected, especially in combination with defects resulting from Cre mediated deletion of any gene under investigation. To further investigate the origin of this phenotype, we re-examined the activity of the transgene. We compared it with expression of Nestin itself in the context of the hypothalamo-pituitary axis, especially in the light of a recent report showing pituitary Nestin-Cre activity, which contrasts with previous data. Our results disagree with those of this recent study and do not support the claim that Nestin positive cells are present in the pituitary anlagen, the Rathke's pouch (RP). Moreover we did not observe any significant activity in the post-natal pituitary, in agreement with the initial report.

No abstract

Astrocytes are necessary for neuronal functionality in the adult brain; but may also support embryonic development of its cytoarchitecture. They are generated after neurons from embryonic radial glial cells, following the gliogenic switch. Regulation of the switch, operated by several transcription factors, is fundamental for allowing coordinated interactions between neurons and glia. We deleted one such factor, Sox9, early during mouse brain development and observed perturbed astrogenesis and a significantly compromised dentate gyrus (DG). We dissected the origin of the defect, targeting Sox9 deletion to either the DG neuronal progenitor domain or the adjacent cortical hem (CH), and identified previously uncharacterized ALDH1L1+ astrocytic progenitors in the CH, which form a fimbrial-specific glial scaffold necessary for neuronal progenitor migration towards the developing DG. Our results highlight the crucial role of SOX9 for astroglial potential and illustrate how formation of a local network, amidst cells originating from adjacent domains, underlays brain morphogenesis.

During embryonic development, radial glial cells give rise to neurons, then to astrocytes following the gliogenic switch. Timely regulation of the switch, operated by several transcription factors, is fundamental for allowing coordinated interactions between neurons and glia. We deleted the gene for one such factor, SOX9, early during mouse brain development and observed a significantly compromised dentate gyrus (DG). We dissected the origin of the defect, targeting embryonic Sox9 deletion to either the DG neuronal progenitor domain or the adjacent cortical hem (CH). We identified in the latter previously uncharacterized ALDH1L1+ astrocytic progenitors, which form a fimbrial-specific glial scaffold necessary for neuronal progenitor migration toward the developing DG. Our results highlight an early crucial role of SOX9 for DG development through regulation of astroglial potential acquisition in the CH. Moreover, we illustrate how formation of a local network, amidst astrocytic and neuronal progenitors originating from adjacent domains, underlays brain morphogenesis.