Sox1 marks an activated neural stem/progenitor cell in the hippocampus
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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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.Neurobiology of Aging 08/2014; DOI:10.1016/j.neurobiolaging.2014.07.033 · 4.85 Impact Factor
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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.Gene Expression Patterns 05/2013; DOI:10.1016/j.gep.2013.04.004 · 1.36 Impact Factor
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ABSTRACT: Glial cells can be in vivo reprogrammed into functional neurons in the adult CNS; however, the process by which this reprogramming occurs is unclear. Here, we show that a distinct cellular sequence is involved in SOX2-driven in situ conversion of adult astrocytes to neurons. This includes ASCL1(+) neural progenitors and DCX(+) adult neuroblasts (iANBs) as intermediates. Importantly, ASCL1 is required, but not sufficient, for the robust generation of iANBs in the adult striatum. These progenitor-derived iANBs predominantly give rise to calretinin(+) interneurons when supplied with neurotrophic factors or the small-molecule valproic acid. Patch-clamp recordings from the induced neurons reveal subtype heterogeneity, though all are functionally mature, fire repetitive action potentials, and receive synaptic inputs. Together, these results show that SOX2-mediated in vivo reprogramming of astrocytes to neurons passes through proliferative intermediate progenitors, which may be exploited for regenerative medicine. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.Stem Cell Reports 05/2015; 4:1-15. DOI:10.1016/j.stemcr.2015.03.006