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• W1987171954 abstract "•SOX2 induces ASCL1-positive neural progenitors in the adult mouse brain•Ascl1 in resident astrocytes is required for SOX2-mediated in vivo reprogramming•Induced ASCL1-positive neural progenitors generate mature calretinin neurons 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. 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. Neurons in the CNS are particularly sensitive to injury and degenerative conditions that frequently result in cell death. Although adult neurogenesis persists in restricted brain areas (Gage, 2000Gage F.H. Mammalian neural stem cells.Science. 2000; 287: 1433-1438Crossref PubMed Scopus (4110) Google Scholar, Hsieh, 2012Hsieh J. Orchestrating transcriptional control of adult neurogenesis.Genes Dev. 2012; 26: 1010-1021Crossref PubMed Scopus (157) Google Scholar, Kriegstein and Alvarez-Buylla, 2009Kriegstein A. Alvarez-Buylla A. The glial nature of embryonic and adult neural stem cells.Annu. Rev. Neurosci. 2009; 32: 149-184Crossref PubMed Scopus (1661) Google Scholar, Lie et al., 2004Lie D.C. Song H. Colamarino S.A. Ming G.L. Gage F.H. Neurogenesis in the adult brain: new strategies for central nervous system diseases.Annu. Rev. Pharmacol. Toxicol. 2004; 44: 399-421Crossref PubMed Scopus (530) Google Scholar), neurons do not regenerate in most regions of the adult CNS. An unmet challenge in neural injury and degeneration repair is how to replenish lost neurons for functional recovery. Cell fate reprogramming provides new means for regenerating damaged or dead neurons (Arlotta and Berninger, 2014Arlotta P. Berninger B. Brains in metamorphosis: reprogramming cell identity within the central nervous system.Curr. Opin. Neurobiol. 2014; 27: 208-214Crossref PubMed Scopus (24) Google Scholar, Cherry and Daley, 2012Cherry A.B. Daley G.Q. Reprogramming cellular identity for regenerative medicine.Cell. 2012; 148: 1110-1122Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar, Matsui et al., 2014Matsui T. Akamatsu W. Nakamura M. Okano H. Regeneration of the damaged central nervous system through reprogramming technology: basic concepts and potential application for cell replacement therapy.Exp. Neurol. 2014; 260: 12-18Crossref PubMed Scopus (25) Google Scholar). Not only can cells in culture be reprogrammed into pluripotent stem cells (Takahashi and Yamanaka, 2006Takahashi K. Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.Cell. 2006; 126: 663-676Abstract Full Text Full Text PDF PubMed Scopus (19243) Google Scholar), lineage-restricted stem cells (Kim et al., 2011aKim J. Efe J.A. Zhu S. Talantova M. Yuan X. Wang S. Lipton S.A. Zhang K. Ding S. Direct reprogramming of mouse fibroblasts to neural progenitors.Proc. Natl. Acad. Sci. USA. 2011; 108: 7838-7843Crossref PubMed Scopus (486) Google Scholar, Ring et al., 2012Ring K.L. Tong L.M. Balestra M.E. Javier R. Andrews-Zwilling Y. Li G. Walker D. Zhang W.R. Kreitzer A.C. Huang Y. Direct reprogramming of mouse and human fibroblasts into multipotent neural stem cells with a single factor.Cell Stem Cell. 2012; 11: 100-109Abstract Full Text Full Text PDF PubMed Scopus (417) Google Scholar), and different postmitotic cell fates (Heinrich et al., 2010Heinrich C. Blum R. Gascón S. Masserdotti G. Tripathi P. Sánchez R. Tiedt S. Schroeder T. Götz M. Berninger B. Directing astroglia from the cerebral cortex into subtype specific functional neurons.PLoS Biol. 2010; 8: e1000373Crossref PubMed Scopus (355) Google Scholar, Heinrich et al., 2011Heinrich C. Gascón S. Masserdotti G. Lepier A. Sanchez R. Simon-Ebert T. Schroeder T. Götz M. Berninger B. Generation of subtype-specific neurons from postnatal astroglia of the mouse cerebral cortex.Nat. Protoc. 2011; 6: 214-228Crossref PubMed Scopus (105) Google Scholar, Karow et al., 2012Karow M. Sánchez R. Schichor C. Masserdotti G. Ortega F. Heinrich C. Gascón S. Khan M.A. Lie D.C. Dellavalle A. et al.Reprogramming of pericyte-derived cells of the adult human brain into induced neuronal cells.Cell Stem Cell. 2012; 11: 471-476Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar, Liu et al., 2013Liu M.L. Zang T. Zou Y. Chang J.C. Gibson J.R. Huber K.M. Zhang C.L. Small molecules enable neurogenin 2 to efficiently convert human fibroblasts into cholinergic neurons.Nat Commun. 2013; 4: 2183PubMed Google Scholar, Vierbuchen et al., 2010Vierbuchen T. Ostermeier A. Pang Z.P. Kokubu Y. Südhof T.C. Wernig M. Direct conversion of fibroblasts to functional neurons by defined factors.Nature. 2010; 463: 1035-1041Crossref PubMed Scopus (2298) Google Scholar), but they are also amenable to in vivo fate conversion (Guo et al., 2014Guo Z. Zhang L. Wu Z. Chen Y. Wang F. Chen G. In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer’s disease model.Cell Stem Cell. 2014; 14: 188-202Abstract Full Text Full Text PDF PubMed Scopus (528) Google Scholar, Heinrich et al., 2014Heinrich C. Bergami M. Gascón S. Lepier A. Viganò F. Dimou L. Sutor B. Berninger B. Götz M. Sox2-mediated conversion of NG2 glia into induced neurons in the injured adult cerebral cortex.Stem Cell Reports. 2014; 3: 1000-1014Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar, Niu et al., 2013Niu W. Zang T. Zou Y. Fang S. Smith D.K. Bachoo R. Zhang C.L. In vivo reprogramming of astrocytes to neuroblasts in the adult brain.Nat. Cell Biol. 2013; 15: 1164-1175Crossref PubMed Scopus (345) Google Scholar, Qian et al., 2012Qian L. Huang Y. Spencer C.I. Foley A. Vedantham V. Liu L. Conway S.J. Fu J.D. Srivastava D. In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes.Nature. 2012; 485: 593-598Crossref PubMed Scopus (1035) Google Scholar, Song et al., 2012Song K. Nam Y.J. Luo X. Qi X. Tan W. Huang G.N. Acharya A. Smith C.L. Tallquist M.D. Neilson E.G. et al.Heart repair by reprogramming non-myocytes with cardiac transcription factors.Nature. 2012; 485: 599-604Crossref PubMed Scopus (882) Google Scholar, Su et al., 2014aSu Z. Niu W. Liu M.L. Zou Y. Zhang C.L. In vivo conversion of astrocytes to neurons in the injured adult spinal cord.Nat Commun. 2014; 5: 3338Crossref PubMed Scopus (278) Google Scholar, Su et al., 2014bSu Z. Zang T. Liu M.L. Wang L.L. Niu W. Zhang C.L. Reprogramming the fate of human glioma cells to impede brain tumor development.Cell Death Dis. 2014; 5: e1463Crossref PubMed Scopus (43) Google Scholar, Torper et al., 2013Torper O. Pfisterer U. Wolf D.A. Pereira M. Lau S. Jakobsson J. Björklund A. Grealish S. Parmar M. Generation of induced neurons via direct conversion in vivo.Proc. Natl. Acad. Sci. USA. 2013; 110: 7038-7043Crossref PubMed Scopus (317) Google Scholar, Zhou et al., 2008Zhou Q. Brown J. Kanarek A. Rajagopal J. Melton D.A. In vivo reprogramming of adult pancreatic exocrine cells to beta-cells.Nature. 2008; 455: 627-632Crossref PubMed Scopus (1661) Google Scholar). In regards to the CNS, resident glial cells have been directly or indirectly converted into functional neurons in the adult brain and spinal cord (Guo et al., 2014Guo Z. Zhang L. Wu Z. Chen Y. Wang F. Chen G. In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer’s disease model.Cell Stem Cell. 2014; 14: 188-202Abstract Full Text Full Text PDF PubMed Scopus (528) Google Scholar, Heinrich et al., 2014Heinrich C. Bergami M. Gascón S. Lepier A. Viganò F. Dimou L. Sutor B. Berninger B. Götz M. Sox2-mediated conversion of NG2 glia into induced neurons in the injured adult cerebral cortex.Stem Cell Reports. 2014; 3: 1000-1014Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar, Niu et al., 2013Niu W. Zang T. Zou Y. Fang S. Smith D.K. Bachoo R. Zhang C.L. In vivo reprogramming of astrocytes to neuroblasts in the adult brain.Nat. Cell Biol. 2013; 15: 1164-1175Crossref PubMed Scopus (345) Google Scholar, Su et al., 2014aSu Z. Niu W. Liu M.L. Zou Y. Zhang C.L. In vivo conversion of astrocytes to neurons in the injured adult spinal cord.Nat Commun. 2014; 5: 3338Crossref PubMed Scopus (278) Google Scholar, Su et al., 2014bSu Z. Zang T. Liu M.L. Wang L.L. Niu W. Zhang C.L. Reprogramming the fate of human glioma cells to impede brain tumor development.Cell Death Dis. 2014; 5: e1463Crossref PubMed Scopus (43) Google Scholar, Torper et al., 2013Torper O. Pfisterer U. Wolf D.A. Pereira M. Lau S. Jakobsson J. Björklund A. Grealish S. Parmar M. Generation of induced neurons via direct conversion in vivo.Proc. Natl. Acad. Sci. USA. 2013; 110: 7038-7043Crossref PubMed Scopus (317) Google Scholar). Glial cells are broadly distributed and comprise nearly half of the cells in the mammalian CNS. These cells become reactive, proliferate, and form glial scars in response to neural injuries and degeneration (Karimi-Abdolrezaee and Billakanti, 2012Karimi-Abdolrezaee S. Billakanti R. Reactive astrogliosis after spinal cord injury-beneficial and detrimental effects.Mol. Neurobiol. 2012; 46: 251-264Crossref PubMed Scopus (245) Google Scholar, Sofroniew, 2009Sofroniew M.V. Molecular dissection of reactive astrogliosis and glial scar formation.Trends Neurosci. 2009; 32: 638-647Abstract Full Text Full Text PDF PubMed Scopus (1852) Google Scholar). These reactive responses are initially beneficial, restricting the spread of damage, but ultimately are deleterious, acting as both a physical and chemical barrier to neuronal regeneration (Karimi-Abdolrezaee and Billakanti, 2012Karimi-Abdolrezaee S. Billakanti R. Reactive astrogliosis after spinal cord injury-beneficial and detrimental effects.Mol. Neurobiol. 2012; 46: 251-264Crossref PubMed Scopus (245) Google Scholar, Sofroniew, 2009Sofroniew M.V. Molecular dissection of reactive astrogliosis and glial scar formation.Trends Neurosci. 2009; 32: 638-647Abstract Full Text Full Text PDF PubMed Scopus (1852) Google Scholar). Reprogramming some of these glial cells to functional neurons may constitute a novel therapeutic strategy for diseases associated with the CNS. Through in vivo screens of candidate factors that are able to induce neurogenesis in non-neurogenic regions of the adult brain and spinal cord, we previously showed that the ectopic expression of SOX2 is sufficient to reprogram resident astrocytes to DCX+ induced adult neuroblasts (iANBs) (Niu et al., 2013Niu W. Zang T. Zou Y. Fang S. Smith D.K. Bachoo R. Zhang C.L. In vivo reprogramming of astrocytes to neuroblasts in the adult brain.Nat. Cell Biol. 2013; 15: 1164-1175Crossref PubMed Scopus (345) Google Scholar, Su et al., 2014aSu Z. Niu W. Liu M.L. Zou Y. Zhang C.L. In vivo conversion of astrocytes to neurons in the injured adult spinal cord.Nat Commun. 2014; 5: 3338Crossref PubMed Scopus (278) Google Scholar). These iANBs pass through a proliferative state and generate mature neurons when supplied with neurotrophic factors. This SOX2-driven in vivo reprogramming process sharply contrasts direct lineage conversion strategies (Guo et al., 2014Guo Z. Zhang L. Wu Z. Chen Y. Wang F. Chen G. In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer’s disease model.Cell Stem Cell. 2014; 14: 188-202Abstract Full Text Full Text PDF PubMed Scopus (528) Google Scholar, Qian et al., 2012Qian L. Huang Y. Spencer C.I. Foley A. Vedantham V. Liu L. Conway S.J. Fu J.D. Srivastava D. In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes.Nature. 2012; 485: 593-598Crossref PubMed Scopus (1035) Google Scholar, Song et al., 2012Song K. Nam Y.J. Luo X. Qi X. Tan W. Huang G.N. Acharya A. Smith C.L. Tallquist M.D. Neilson E.G. et al.Heart repair by reprogramming non-myocytes with cardiac transcription factors.Nature. 2012; 485: 599-604Crossref PubMed Scopus (882) Google Scholar, Su et al., 2014bSu Z. Zang T. Liu M.L. Wang L.L. Niu W. Zhang C.L. Reprogramming the fate of human glioma cells to impede brain tumor development.Cell Death Dis. 2014; 5: e1463Crossref PubMed Scopus (43) Google Scholar, Torper et al., 2013Torper O. Pfisterer U. Wolf D.A. Pereira M. Lau S. Jakobsson J. Björklund A. Grealish S. Parmar M. Generation of induced neurons via direct conversion in vivo.Proc. Natl. Acad. Sci. USA. 2013; 110: 7038-7043Crossref PubMed Scopus (317) Google Scholar, Zhou et al., 2008Zhou Q. Brown J. Kanarek A. Rajagopal J. Melton D.A. In vivo reprogramming of adult pancreatic exocrine cells to beta-cells.Nature. 2008; 455: 627-632Crossref PubMed Scopus (1661) Google Scholar), which change cell fate in a linear fashion without amplification of the induced cell population. However, the cellular mechanism underlying SOX2-dependent in vivo reprogramming of astrocytes was unclear. Furthermore, the subtypes of iANB-derived neurons were not well characterized. In this study, we reveal that SOX2-driven reprogramming of astrocytes transits through intermediate neural progenitor states before the adoption of a mature neuron fate. Immunohistochemistry and electrophysiology further show that induced neurons are functionally mature and predominantly express the marker calretinin. SOX2 belongs to the SOXB1 subfamily of high-mobility group-box transcription factors, which also includes SOX1 and SOX3 (Sarkar and Hochedlinger, 2013Sarkar A. Hochedlinger K. The sox family of transcription factors: versatile regulators of stem and progenitor cell fate.Cell Stem Cell. 2013; 12: 15-30Abstract Full Text Full Text PDF PubMed Scopus (636) Google Scholar). These factors are critical for specifying and maintaining the undifferentiated state of neural precursors. The expression of SOXB1 factors during SOX2-mediated in vivo reprogramming were investigated using immunohistochemistry (Niu et al., 2013Niu W. Zang T. Zou Y. Fang S. Smith D.K. Bachoo R. Zhang C.L. In vivo reprogramming of astrocytes to neuroblasts in the adult brain.Nat. Cell Biol. 2013; 15: 1164-1175Crossref PubMed Scopus (345) Google Scholar). The adult mouse striatum was injected with lentivirus expressing SOX2 under the human GFAP promoter. When analyzed 4 weeks post-injection (wpi), DCX+ iANBs were robustly detected in the virus-injected regions, confirming our previous results (Niu et al., 2013Niu W. Zang T. Zou Y. Fang S. Smith D.K. Bachoo R. Zhang C.L. In vivo reprogramming of astrocytes to neuroblasts in the adult brain.Nat. Cell Biol. 2013; 15: 1164-1175Crossref PubMed Scopus (345) Google Scholar). Interestingly, SOX1 can also be detected in striatal regions with iANBs, especially in DCX+ cell clusters (Figure 1A). However, SOX1 expression is lower in iANBs than neighboring DCX− cells, which is consistent with previous findings that the continued high-level expression of SOXB1 factors prohibits neuronal differentiation (Bylund et al., 2003Bylund M. Andersson E. Novitch B.G. Muhr J. Vertebrate neurogenesis is counteracted by Sox1-3 activity.Nat. Neurosci. 2003; 6: 1162-1168Crossref PubMed Scopus (645) Google Scholar, Niu et al., 2013Niu W. Zang T. Zou Y. Fang S. Smith D.K. Bachoo R. Zhang C.L. In vivo reprogramming of astrocytes to neuroblasts in the adult brain.Nat. Cell Biol. 2013; 15: 1164-1175Crossref PubMed Scopus (345) Google Scholar). In contrast, SOX3 is only sporadically distributed in the adult striatum and is not detectable in DCX+ iANBs (Figure 1A). Due to sequence and potential functional similarity (Bylund et al., 2003Bylund M. Andersson E. Novitch B.G. Muhr J. Vertebrate neurogenesis is counteracted by Sox1-3 activity.Nat. Neurosci. 2003; 6: 1162-1168Crossref PubMed Scopus (645) Google Scholar), we investigated whether the SOXB1 proteins can similarly induce DCX+ cells. Lentiviruses expressing SOX1 or SOX3 under the GFAP promoter were individually injected into the adult striatum. However, when examined at 4 or 5 wpi, no DCX+ cells were detected in striatal regions with ectopic SOX1 or SOX3 expression, in sharp contrast to areas injected with SOX2-expressing virus that contain DCX+ cells (Figure 1B). Together, these data indicate that SOX2 has a unique property among the SOXB1 factors, enabling the reprogramming of resident astrocytes to iANBs. SOX2-dependent iANBs in the adult striatum were further examined by injections of lentivirus expressing GFP-T2A-SOX2 under the GFAP promoter (Figure S1). The co-expressed stable GFP marked virus-transduced cells. Immunohistochemical analysis showed that about 23.2% ± 5.3% of GFP+ cells (mean ± SD; n = 17,841 GFP+ cells counted in sections from three mice) stained positive for DCX (Figure S1). This suggests a relatively efficient induction of iANBs from SOX2-expressing cells. Adult neurogenesis is a multistep process that starts with multipotent neural stem cells (NSCs) that gradually transition into DCX+ neuroblasts (Hsieh, 2012Hsieh J. Orchestrating transcriptional control of adult neurogenesis.Genes Dev. 2012; 26: 1010-1021Crossref PubMed Scopus (157) Google Scholar, Kempermann et al., 2004Kempermann G. Jessberger S. Steiner B. Kronenberg G. Milestones of neuronal development in the adult hippocampus.Trends Neurosci. 2004; 27: 447-452Abstract Full Text Full Text PDF PubMed Scopus (1150) Google Scholar, Kriegstein and Alvarez-Buylla, 2009Kriegstein A. Alvarez-Buylla A. The glial nature of embryonic and adult neural stem cells.Annu. Rev. Neurosci. 2009; 32: 149-184Crossref PubMed Scopus (1661) Google Scholar, Ma et al., 2009Ma D.K. Bonaguidi M.A. Ming G.L. Song H. Adult neural stem cells in the mammalian central nervous system.Cell Res. 2009; 19: 672-682Crossref PubMed Scopus (241) Google Scholar). Both SOX1 and SOX2 are expressed in NSCs that can give rise to neurons and glia (Suh et al., 2007Suh H. Consiglio A. Ray J. Sawai T. D’Amour K.A. Gage F.H. In vivo fate analysis reveals the multipotent and self-renewal capacities of Sox2+ neural stem cells in the adult hippocampus.Cell Stem Cell. 2007; 1: 515-528Abstract Full Text Full Text PDF PubMed Scopus (627) Google Scholar, Venere et al., 2012Venere M. Han Y.G. Bell R. Song J.S. Alvarez-Buylla A. Blelloch R. Sox1 marks an activated neural stem/progenitor cell in the hippocampus.Development. 2012; 139: 3938-3949Crossref PubMed Scopus (63) Google Scholar). The residual expression of these factors in DCX+ iANBs suggests that ectopic SOX2 might reprogram astrocytes into a multipotent NSC state. We surveyed the expression of several additional markers for NSCs surrounding striatal regions injected with SOX2-expressing virus at 4 wpi. Nestin (NES), an intermediate filament protein highly enriched in embryonic and adult NSCs (Lagace et al., 2007Lagace D.C. Whitman M.C. Noonan M.A. Ables J.L. DeCarolis N.A. Arguello A.A. Donovan M.H. Fischer S.J. Farnbauch L.A. Beech R.D. et al.Dynamic contribution of nestin-expressing stem cells to adult neurogenesis.J. Neurosci. 2007; 27: 12623-12629Crossref PubMed Scopus (387) Google Scholar), can be sparsely detected in neighboring regions with iANBs (Figure S2). Similarly, cells expressing brain-lipid-binding protein, a marker for radial glia in developing brain and type-1 and type-2 neural precursors of the adult dentate gyrus (DG) (Feng et al., 1994Feng L. Hatten M.E. Heintz N. Brain lipid-binding protein (BLBP): a novel signaling system in the developing mammalian CNS.Neuron. 1994; 12: 895-908Abstract Full Text PDF PubMed Scopus (465) Google Scholar, Steiner et al., 2006Steiner B. Klempin F. Wang L. Kott M. Kettenmann H. Kempermann G. Type-2 cells as link between glial and neuronal lineage in adult hippocampal neurogenesis.Glia. 2006; 54: 805-814Crossref PubMed Scopus (279) Google Scholar), are intermingled with iANBs in the adult striatum. GFAP+ cells are also found in the vicinity of iANBs (Figure S2). GFAP is robustly induced in reactive astrocytes and also labels NSCs in the adult lateral ventricle (LV) and DG (Doetsch, 2003Doetsch F. The glial identity of neural stem cells.Nat. Neurosci. 2003; 6: 1127-1134Crossref PubMed Scopus (610) Google Scholar, Kriegstein and Alvarez-Buylla, 2009Kriegstein A. Alvarez-Buylla A. The glial nature of embryonic and adult neural stem cells.Annu. Rev. Neurosci. 2009; 32: 149-184Crossref PubMed Scopus (1661) Google Scholar, Lie et al., 2004Lie D.C. Song H. Colamarino S.A. Ming G.L. Gage F.H. Neurogenesis in the adult brain: new strategies for central nervous system diseases.Annu. Rev. Pharmacol. Toxicol. 2004; 44: 399-421Crossref PubMed Scopus (530) Google Scholar). Although the above markers were not detected in DCX+ cells, these data support a hypothesis that iANBs might be derived from SOX2-induced NSCs in the striatum. We directly examined this hypothesis using a lineage-tracing strategy. When adult Nes-CreERTM;Rosa-YFP mice were treated with tamoxifen for 7 days and examined 3 weeks later, DCX+ cells in the LV and DG were robustly labeled with the YFP reporter (Figures 2A and 2B ). This result confirms that neuroblasts from endogenous NSCs can be specifically traced in this transgenic mouse line (Kuo et al., 2006Kuo C.T. Mirzadeh Z. Soriano-Navarro M. Rasin M. Wang D. Shen J. Sestan N. Garcia-Verdugo J. Alvarez-Buylla A. Jan L.Y. Jan Y.N. Postnatal deletion of Numb/Numblike reveals repair and remodeling capacity in the subventricular neurogenic niche.Cell. 2006; 127: 1253-1264Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar, Niu et al., 2013Niu W. Zang T. Zou Y. Fang S. Smith D.K. Bachoo R. Zhang C.L. In vivo reprogramming of astrocytes to neuroblasts in the adult brain.Nat. Cell Biol. 2013; 15: 1164-1175Crossref PubMed Scopus (345) Google Scholar). We then injected SOX2-expressing lentivirus into the striatum of adult Nes-CreERTM;Rosa-YFP mice, administered tamoxifen at 2 or 3 wpi, and performed immunohistochemistry after another 3 weeks. As internal controls, endogenous neuroblasts in the LV were traced with the marker YFP. In sharp contrast, none of the SOX2-induced DCX+ cells in the striatum were YFP labeled, indicating that ectopic SOX2 does not reprogram astrocytes into a NSC-like state (Figures 2C and 2D). ASCL1+ neural progenitors precede the development of DCX+ neuroblasts during adult neurogenesis (Kim et al., 2011aKim J. Efe J.A. Zhu S. Talantova M. Yuan X. Wang S. Lipton S.A. Zhang K. Ding S. Direct reprogramming of mouse fibroblasts to neural progenitors.Proc. Natl. Acad. Sci. USA. 2011; 108: 7838-7843Crossref PubMed Scopus (486) Google Scholar, Lugert et al., 2012Lugert S. Vogt M. Tchorz J.S. Müller M. Giachino C. Taylor V. Homeostatic neurogenesis in the adult hippocampus does not involve amplification of Ascl1(high) intermediate progenitors.Nat Commun. 2012; 3: 670Crossref PubMed Scopus (72) Google Scholar). Very interestingly, ASCL1+ cells can be specifically detected in the striatal regions around DCX+ iANBs when injected with SOX2, but not a control virus, at 5 wpi (Figure 3A). A time course analysis further showed that the number of ASCL+ cells gradually increases post-injection of SOX2 virus, reaches a peak level around 5 wpi, and persists beyond 14 wpi (Figure 3B). We used the GFAP-GFP marker to label virus-transduced astrocytes in the adult striatum and revealed specific ASCL1 expression in these GFP+ cells, which clustered with SOX2-induced DCX+ cells (Figure 3C). The above results suggest that ASCL1+ cells might be the precursors of iANBs during SOX2-driven in vivo astrocyte reprogramming. We examined this possibility using Ascl1-CreERT2 mice, in which the tamoxifen-inducible CreERT2 was knocked into the endogenous Ascl1 locus (Kim et al., 2011bKim E.J. Ables J.L. Dickel L.K. Eisch A.J. Johnson J.E. Ascl1 (Mash1) defines cells with long-term neurogenic potential in subgranular and subventricular zones in adult mouse brain.PLoS ONE. 2011; 6: e18472Crossref PubMed Scopus (174) Google Scholar). After crossing to mice harboring the Cre-activity-dependent Rosa-tdTomato (tdT) reporter (Madisen et al., 2010Madisen L. Zwingman T.A. Sunkin S.M. Oh S.W. Zariwala H.A. Gu H. Ng L.L. Palmiter R.D. Hawrylycz M.J. Jones A.R. et al.A robust and high-throughput Cre reporting and characterization system for the whole mouse brain.Nat. Neurosci. 2010; 13: 133-140Crossref PubMed Scopus (3983) Google Scholar), ASCL1+ cells and their progeny can be uniquely traced. These adult mice were injected with a SOX2-expressing or control virus, administered tamoxifen for 7 days starting at 2 wpi, and examined at 6 wpi (Figure 3D). Whereas no tdT+ cells were detected in striatal regions injected with the control virus, these cells were robustly distributed in regions injected with the SOX2 virus (Figure 3E). Consistent with the hypothesis that iANBs are derived from ASCL1+ neural progenitors, over 90% of SOX2-induced DCX+ cells could be labeled by tdT. Together, these data show that ectopic SOX2 reprograms striatal astrocytes to ASCL1+ neural progenitors, which subsequently give rise to DCX+ iANBs. ASCL1 is a neural specific basic helix-loop-helix transcription factor and essential for neurogenesis during early nervous system development (Casarosa et al., 1999Casarosa S. Fode C. Guillemot F. Mash1 regulates neurogenesis in the ventral telencephalon.Development. 1999; 126: 525-534Crossref PubMed Google Scholar, Nieto et al., 2001Nieto M. Schuurmans C. Britz O. Guillemot F. Neural bHLH genes control the neuronal versus glial fate decision in cortical progenitors.Neuron. 2001; 29: 401-413Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar, Torii et al., 1999Torii Ma. Matsuzaki F. Osumi N. Kaibuchi K. Nakamura S. Casarosa S. Guillemot F. Nakafuku M. Transcription factors Mash-1 and Prox-1 delineate early steps in differentiation of neural stem cells in the developing central nervous system.Development. 1999; 126: 443-456Crossref PubMed Google Scholar). The induction of ASCL1 in the adult striatum suggests that it may be critical for SOX2-driven in vivo reprogramming of astrocytes. To examine this possibility, we used genetically modified mice that contain conditional alleles of Ascl1 (Ascl1f/f; Pacary et al., 2011Pacary E. Heng J. Azzarelli R. Riou P. Castro D. Lebel-Potter M. Parras C. Bell D.M. Ridley A.J. Parsons M. Guillemot F. Proneural transcription factors regulate different steps of cortical neuron migration through Rnd-mediated inhibition of RhoA signaling.Neuron. 2011; 69: 1069-1084Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar) and a tamoxifen-inducible CreERT2 transgene under the astrocyte-specific Cst3 promoter (Figure 4A) (Niu et al., 2013Niu W. Zang T. Zou Y. Fang S. Smith D.K. Bachoo R. Zhang C.L. In vivo reprogramming of astrocytes to neuroblasts in the adult brain.Nat. Cell Biol. 2013; 15: 1164-1175Crossref PubMed Scopus (345) Google Scholar). These adult mice were treated with tamoxifen or vehicle for 7 days and then injected with SOX2-expressing lentivirus. Immunohistochemistry was performed 5 wpi and revealed a dramatic reduction in the population of DCX+ iANBs upon inducible deletion of Ascl1 (Figures 4B and 4C). The few residual DCX+ cells might be due to an incomplete deletion of Ascl1 in all the SOX2 virus-infected astrocytes. These data indicate that ASCL1 plays a critical role in SOX2-driven reprogramming. Ectopic ASCL1 is sufficient to promote the neuronal differentiation of embryonic stem cells and NSCs (Berninger et al., 2007Berninger B. Guillemot F. Götz M. Directing neurotransmitter identity of neurones derived from expanded adult neural stem cells.Eur. J. Neurosci. 2007; 25: 2581-2590Crossref PubMed Scopus (70) Google Scholar, Chanda et al., 2014Chanda S. Ang C.E. Davila J. Pak C. Mall M. Lee Q.Y. Ahlenius H. Jung S.W. Südhof T.C. Wernig M. Generation of induced neuronal cells by the single reprogramming factor ASCL1.Stem Cell Rev. 2014; 3: 282-296Abstract Full Text Full Text PDF Scopus (244) Google Scholar), as well as reprogram cultured fibroblasts and early postnatal astroglia to neurons (Chanda et al., 2014Chanda S. Ang C.E. Davila J. Pak C. Mall M. Lee Q.Y. Ahlenius H. Jung S.W. Südhof T.C. Wernig M. Generation of induced neuronal cells by the single reprogramming factor ASCL1.Stem Cell Rev." @default.
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• W1987171954 title "SOX2 Reprograms Resident Astrocytes into Neural Progenitors in the Adult Brain" @default.
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