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Sox1 marks an activated neural stem/progenitor cell in the hippocampus

Department of Urology, University of California, San Francisco, CA 94143, USA.
Development (Impact Factor: 6.27). 09/2012; 139(21):3938-49. DOI: 10.1242/dev.081133
Source: PubMed

ABSTRACT The dentate gyrus of the hippocampus continues generating new neurons throughout life. These neurons originate from radial astrocytes within the subgranular zone (SGZ). Here, we find that Sox1, a member of the SoxB1 family of transcription factors, is expressed in a subset of radial astrocytes. Lineage tracing using Sox1-tTA;tetO-Cre;Rosa26 reporter mice shows that the Sox1-expressing cells represent an activated neural stem/progenitor population that gives rise to most if not all newly born granular neurons, as well as a small number of mature hilar astrocytes. Furthermore, a subpopulation of Sox1-marked cells have long-term neurogenic potential, producing new neurons 3 months after inactivation of tetracycline transactivator. Remarkably, after 8 weeks of labeling and a 12-week chase, as much as 44% of all granular neurons in the dentate gyrus were derived from Sox1 lineage-traced adult neural stem/progenitor cells. The fraction of Sox1-positive cells within the radial astrocyte population decreases with age, correlating with a decrease in neurogenesis. However, expression profiling shows that these cells are transcriptionally stable throughout the lifespan of the mouse. These results demonstrate that Sox1 is expressed in an activated stem/progenitor population whose numbers decrease with age while maintaining a stable molecular program.

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    • "he total size of earlier " progenitor " cells by quantifying changes in Sox1 - expressing cell numbers within the hippocampal SGZ . Sox1 expression is critical in maintaining NPCs in a non - committed state ( Bylund et al . , 2003 ) , marking an activated popu - lation of early NPCs that gives rise to most , if not all , newborn granular neurons ( Venere et al . , 2012 ) . Notably , as Sox1 directly activates Nestin - enhancer elements , Sox1 expression precedes the appearance of Nestin ( Kan et al . , 2004 ; Tanaka et al . , 2004 ) ."
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    ABSTRACT: Adult hippocampal neurogenesis drastically diminishes with age but the underlying mechanisms remain unclear. Here, age-related influences on the hippocampal early neuroprogenitor cell (NPC) pool was examined by quantifying changes in Sox1-expressing cells in the dentate gyrus (DG) subgranular zone from early adulthood (3 months) to middle age (12 months). Proliferation of distinct NPC subpopulations (Sox1+, Nestin+ and Doublecortin+) and newborn cell survival were also investigated. Examination of total BrdU+ and Doublecortin+ (DCX) cells revealed an early and dramatic age-dependent decline of hippocampal neurogenesis. Increasing age from 3 to 12 months was primarily associated with reduced total proliferation, in vivo (-79% of BrdU+ cells) but not in vitro, and DCX+ cell numbers (-89%). When proliferative rates of individual NPC subpopulations were examined, a different picture emerged as proliferating Nestin+ neuroprogenitors (-95% at 9 months) and BrdU+/DCX+ neuroblasts/immature neurons (-83% at 12 months) declined the most, while proliferating Sox1+ NPCs only dropped by 53%. Remarkably, despite greatly reduced proliferative rates and recent reports of Nestin+ neuroprogenitor loss, total numbers of early Sox1+ NPCs were unaffected by age (at least up to middle age) and newborn cell survival within the DG was increased. Neuronal differentiation was concomitantly reduced however, thus suggesting age-associated changes in fate-choice determination.
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    • "We have found a small number of GFAP+Smad3+ cells with a cell body residing in the DG and a radial process extending into the granule layer, however they seems not to be RGL precursors. It is already known the heterogeneity of RGL cells, with subpopulations identified by different markers [36] or properties, such as proliferative or quiescence, although with similar morphology [10]. However, we have found GFAP+Smad3+ cells near vessels, suggesting that they could be astrocytes. "
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    ABSTRACT: New neurons are continuously being generated in the adult hippocampus, a phenomenon that is regulated by external stimuli, such as learning, memory, exercise, environment or stress. However, the molecular mechanisms underlying neuron production and how they are integrated into existing circuits under such physiological conditions remain unclear. Indeed, the intracellular modulators that transduce the extracellular signals are not yet fully understood. We show that Smad3, an intracellular molecule involved in the transforming growth factor (TGF)-beta signaling cascade, is strongly expressed by granule cells in the dentate gyrus (DG) of adult mice, although the loss of Smad3 in null mutant mice does not affect their survival. Smad3 is also expressed by adult progenitor cells in the subgranular zone (SGZ) and more specifically, it is first expressed by Type 2 cells (intermediate progenitor cells). Its expression persists through the distinct cell stages towards that of the mature neuron. Interestingly, proliferative intermediate progenitor cells die in Smad3 deficiency, which is associated with a large decrease in the production of newborn neurons in Smad3 deficient mice. Smad3 signaling appears to influence adult neurogenesis fulfilling distinct roles in the rostral and mid-caudal regions of the DG. In rostral areas, Smad3 deficiency increases proliferation and promotes the cell cycle exit of undifferentiated progenitor cells. By contrast, Smad3 deficiency impairs the survival of newborn neurons in the mid-caudal region of the DG at early proliferative stages, activating apoptosis of intermediate progenitor cells. Furthermore, long-term potentiation (LTP) after high frequency stimulation (HFS) to the medial perforant path (MPP) was abolished in the DG of Smad3-deficient mice. These data show that endogenous Smad3 signaling is central to neurogenesis and LTP induction in the adult DG, these being two forms of hippocampal brain plasticity related to learning and memory that decline with aging and as a result of neurological disorders.
    Cell Communication and Signaling 12/2013; 11(1):93. DOI:10.1186/1478-811X-11-93 · 4.67 Impact Factor
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    • "These data also suggest that adult neurogenesis may be defective in Sox3 null mice. However, the extensive overlap with SOX2 and most likely SOX1 (Venere et al., 2012) would also suggest that any defect, if present, would be subtle within the developed brain. 1.5.3. "
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    ABSTRACT: Previous studies have shown that Sox3 is expressed in nascent neuroprogenitor cells and is functionally required in mammals for development of the dorsal telencephalon and hypothalamus. However, Sox3 expression during embryonic and adult neurogenesis has not been examined in detail. Using a SOX3-specific antibody, we show that murine SOX3 expression is maintained throughout telencephalic neurogenesis and is restricted to progenitor cells with neuroepithelial and radial glial morphologies. We also demonstrate that SOX3 is expressed within the adult neurogenic regions and is coexpressed extensively with the neural stem cell marker SOX2 indicating that it is a lifelong marker of neuroprogenitor cells. In contrast to the telencephalon, Sox3 expression within the developing hypothalamus is upregulated in developing neurons and is maintained in a subset of differentiated hypothalamic cells through to adulthood. Together, these data show that Sox3 regulation is region-specific, consistent with it playing distinct biological roles in the dorsal telencephalon and hypothalamus.
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