SOX2 Reprograms Resident Astrocytes into Neural Progenitors in the Adult Brain

Niu, Wenze; Zang, Tong; Smith, Derek K.; Vue, Tou Yia; Zou, Yuhua; Bachoo, Robert; Johnson, Jane E.; Zhang, Chun Li

doi:10.1016/j.stemcr.2015.03.006

Cited by 190 publications

(191 citation statements)

References 68 publications

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“…It has been shown that SOX2 is important in the maintenance of pluripotency, but it also promotes neural progenitor ground state by inhibiting further neuronal differentiation [54]. More recently, it has been shown that SOX2 expression in astrocytes effectively reprograms these cells to the neural progenitor/precursor stage [55]. Our results show that even partial reduction in FMRP levels is sufficient to induce an increase in SOX2, promoting a delay in neurodevelopment, explaining the more primitive neural phenotype observed in FX-hNPCs than in controls.…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanisms Regulating Impaired Neurogenesis of Fragile X Syndrome Human Embryonic Stem Cells

Telias

Mayshar

Amit

et al. 2015

Stem Cells and Development

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Fragile X syndrome (FXS) is the most common form of inherited cognitive impairment. It is caused by developmental inactivation of the FMR1 gene and the absence of its encoded protein FMRP, which plays pivotal roles in brain development and function. In FXS embryos with full FMR1 mutation, FMRP is expressed during early embryogenesis and is gradually downregulated at the third trimester of pregnancy. FX-human embryonic stem cells (FX-hESCs), derived from FX human blastocysts, demonstrate the same pattern of developmentally regulated FMR1 inactivation when subjected to in vitro neural differentiation (IVND). In this study, we used this in vitro human platform to explore the molecular mechanisms downstream to FMRP in the context of early human embryonic neurogenesis. Our results show a novel role for the SOX superfamily of transcription factors, specifically for SOX2 and SOX9, which could explain the reduced and delayed neurogenesis observed in FX cells. In addition, we assess in this study the ''GSK3b theory of FXS'' for the first time in a human-based model. We found no evidence for a pathological increase in GSK3b protein levels upon cellular loss of FMRP, in contrast to what was found in the brain of Fmr1 knockout mice. Our study adds novel data on potential downstream targets of FMRP and highlights the importance of the FX-hESC IVND system.

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Section: Discussionmentioning

confidence: 99%

Molecular Mechanisms Regulating Impaired Neurogenesis of Fragile X Syndrome Human Embryonic Stem Cells

Telias

Mayshar

Amit

et al. 2015

Stem Cells and Development

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Section: Rit1 Controls Neurogenesismentioning

confidence: 99%

“…In the adult CNS, retroviral delivery of Sox2 has been found to directly or indirectly reprogram resident astrocytes into induced neurons in the injured adult cerebral cortex (45)(46)(47). Importantly, there is a cellular progression for Sox2-mediated conversion of adult astrocytes to neurons, involving the neural commitment of progenitors (46). These induced adult neuroblasts are capable of in vivo proliferation and generate mature neurons when supplied with neurotrophic factors or following small-molecule treatment (46,47), which may provide a novel strategy for neuronal regenerative therapy.…”

Section: Rit1 Controls Neurogenesismentioning

confidence: 99%

“…Importantly, there is a cellular progression for Sox2-mediated conversion of adult astrocytes to neurons, involving the neural commitment of progenitors (46). These induced adult neuroblasts are capable of in vivo proliferation and generate mature neurons when supplied with neurotrophic factors or following small-molecule treatment (46,47), which may provide a novel strategy for neuronal regenerative therapy. Because RIT1 controls neurogenesis and stimulates a Sox2/pro-neurogenic transcriptional program, it will be important in future to examine whether active RIT1 might be used for resident astroglial cell reprogramming.…”

Section: Rit1 Controls Neurogenesismentioning

confidence: 99%

“…Because RIT1 is known to couple diverse neuronal mitogens and cellular stress stimuli to transcriptional activation, an intriguing possibility is that RIT1-mediated Sox2 activation plays a role in neurogenic niche sensing, serving to link select environmental or physiological stimuli to neural stem cell selfrenewal and differentiation. Growing literature indicates that Sox2-dependent reprogramming strategies allow the conversion of glial cells into neurons, allowing the possibility of regenerative cell therapy for repair of the damaged brain (45)(46)(47)(48)(49). Identification of the cellular stimuli that activate RIT1 or inducible delivery of active RIT1 (50) might provide a novel therapeutic repair strategy, especially during states of crisis such as the aftermath of traumatic brain injury.…”

Section: Rit1 Controls Neurogenesismentioning

confidence: 99%

See 2 more Smart Citations

RIT1 GTPase Regulates Sox2 Transcriptional Activity and Hippocampal Neurogenesis

Mir

Cai

Andres

2017

Journal of Biological Chemistry

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Edited by Paul E. FraserAdult neurogenesis, the process of generating mature neurons from neuronal progenitor cells, makes critical contributions to neural circuitry and brain function in both healthy and disease states. Neurogenesis is a highly regulated process in which diverse environmental and physiological stimuli are relayed to resident neural stem cell populations to control the transcription of genes involved in self-renewal and differentiation. Understanding the molecular mechanisms governing neurogenesis is necessary for the development of translational strategies to harness this process for neuronal repair. Here we report that the Ras-related GTPase RIT1 serves to control the sequential proliferation and differentiation of adult hippocampal neural progenitor cells, with in vivo expression of active RIT1 driving robust adult neurogenesis. Gene expression profiling analysis demonstrates increased expression of a specific set of transcription factors known to govern adult neurogenesis in response to active RIT1 expression in the hippocampus, including sex-determining region Y-related HMG box 2 (Sox2), a well established regulator of stem cell self-renewal and neurogenesis. In adult hippocampal neuronal precursor cells, RIT1 controls an Akt-dependent signaling cascade, resulting in the stabilization and transcriptional activation of phosphorylated Sox2. This study supports a role for RIT1 in relaying niche-derived signals to neural/stem progenitor cells to control transcription of genes involved in self-renewal and differentiation.

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Synergistic Enhancement of Adeno‐Associated Virus‐Mediated In Vivo Direct Neuronal Reprogramming by Spatially Aligned Fibrous Matrices in Spinal Cord Injury Models

Kim

Son

Hwang

et al. 2023

Advanced Therapeutics

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In vivo direct neuronal reprogramming approaches, which convert host glial cells into neurons without using exogenous cellular supplies, have become a powerful strategy for neuronal regeneration. However, their effectiveness in severe spinal cord injury (SCI) models with a physical gap between the injured sites is unclear. This study highlights the important role of physical guidance in increasing the therapeutic efficacy of in vivo reprogramming technologies in SCI hemisection models. Reactive astrocytes are selected as host targets for conversion into neurons. An astrocyte‐tropic adeno‐associated viral (AAV) vector, AAVShH19, is used to deliver the neuronal transcription factor NeuroD1 to reactive astrocytes. The infusion of AAVShH19‐NeuroD1 induces astrocyte‐to‐neuron conversion, but improvement of locomotive function is not observed due to the physical distance between the rostral and caudal sides, which impedes axonal extension. To address this issue, electrospun fibrous matrices with adhesive and aligned structural features are implanted into the hemisection cavity and designed to release AAVShH19‐NeuroD1. The combination of the AAV‐mediated reprogramming approach and the matrices promoted astrocyte‐to‐neuron conversion and coordinated the elongation of neuronal axons along the fibers, leading to improved synaptic connections and motor function. This study demonstrates the potential of physical support to enhance the efficacy of direct neuronal reprogramming.

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SOX2 Reprograms Resident Astrocytes into Neural Progenitors in the Adult Brain

Cited by 190 publications

References 68 publications

Molecular Mechanisms Regulating Impaired Neurogenesis of Fragile X Syndrome Human Embryonic Stem Cells

Molecular Mechanisms Regulating Impaired Neurogenesis of Fragile X Syndrome Human Embryonic Stem Cells

RIT1 GTPase Regulates Sox2 Transcriptional Activity and Hippocampal Neurogenesis

Synergistic Enhancement of Adeno‐Associated Virus‐Mediated In Vivo Direct Neuronal Reprogramming by Spatially Aligned Fibrous Matrices in Spinal Cord Injury Models

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