Generation of pure GABAergic neurons by transcription factor programming

Yang, Nan; Chanda, Soham; Marro, Samuele; Ng, Yi-Han; Janas, Justyna A.; Haag, Daniel; Ang, Cheen Euong; Tang, Yunshuo; Flores, Quetzal; Mall, Moritz; Wapinski, Orly L.; Li, Mavis; Ahlenius, Henrik; Rubenstein, John L.R.; Chang, Howard Y.; Alvarez-Buylla, Arturo; Südhof, Thomas C.; Wernig, Marius

doi:10.1038/nmeth.4291

Cited by 277 publications

(172 citation statements)

References 41 publications

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“…Indeed, one limitation observed over the years is the rather protracted period of neuronal maturation from human pluripotent stem cells, which constitutes a major bottleneck for their routine and large-scale application in disease modeling or regenerative medicine. This has been facilitated by improved protocols with accelerated neuronal differentiation either using transcription factors 169 , 170 or small molecules. 160 Alternatively, this obstacle can be overcome by using direct conversion of human fibroblasts into the desired neurons.…”

Section: Transplantation Of Neurons or Neurogenic Cellsmentioning

confidence: 99%

Neuronal replacement therapy: previous achievements and challenges ahead

Grade

Götz

2017

npj Regen Med

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Lifelong neurogenesis and incorporation of newborn neurons into mature neuronal circuits operates in specialized niches of the mammalian brain and serves as role model for neuronal replacement strategies. However, to which extent can the remaining brain parenchyma, which never incorporates new neurons during the adulthood, be as plastic and readily accommodate neurons in networks that suffered neuronal loss due to injury or neurological disease? Which microenvironment is permissive for neuronal replacement and synaptic integration and which cells perform best? Can lost function be restored and how adequate is the participation in the pre-existing circuitry? Could aberrant connections cause malfunction especially in networks dominated by excitatory neurons, such as the cerebral cortex? These questions show how important connectivity and circuitry aspects are for regenerative medicine, which is the focus of this review. We will discuss the impressive advances in neuronal replacement strategies and success from exogenous as well as endogenous cell sources. Both have seen key novel technologies, like the groundbreaking discovery of induced pluripotent stem cells and direct neuronal reprogramming, offering alternatives to the transplantation of fetal neurons, and both herald great expectations. For these to become reality, neuronal circuitry analysis is key now. As our understanding of neuronal circuits increases, neuronal replacement therapy should fulfill those prerequisites in network structure and function, in brain-wide input and output. Now is the time to incorporate neural circuitry research into regenerative medicine if we ever want to truly repair brain injury.

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Section: Transplantation Of Neurons or Neurogenic Cellsmentioning

confidence: 99%

Neuronal replacement therapy: previous achievements and challenges ahead

Grade

Götz

2017

npj Regen Med

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“…N2a cells were seeded into 24-well plates and transfected with 0.2 µg of 8XTOPFLASH reporter and 0.05 µg of pRL-TK, 0.4 µg WT-DISC1 or DN-DISC1 and 0.4 µg mouse DLX2 [ 95 ] using polyethylenimine . 24 hours after transfection, TCF reporter activity was measured using the Dual-Luciferase Assay System (Promega).…”

Section: Methodsmentioning

confidence: 99%

A prenatal interruption of DISC1 function in the brain exhibits a lasting impact on adult behaviors, brain metabolism, and interneuron development

et al. 2017

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Mental illnesses like schizophrenia (SCZ) and major depression disorder (MDD) are devastating brain disorders. The SCZ risk gene, disrupted in schizophrenia 1 (DISC1), has been associated with neuropsychiatric conditions. However, little is known regarding the long-lasting impacts on brain metabolism and behavioral outcomes from genetic insults on fetal NPCs during early life. We have established a new mouse model that specifically interrupts DISC1 functions in NPCs in vivo by a dominant-negative DISC1 (DN-DISC1) with a precise temporal and spatial regulation. Interestingly, prenatal interruption of mouse Disc1 function in NPCs leads to abnormal depression-like deficit in adult mice. Here we took a novel unbiased metabonomics approach to identify brain-specific metabolites that are significantly changed in DN-DISC1 mice. Surprisingly, the inhibitory neurotransmitter, GABA, is augmented. Consistently, parvalbumin (PV) interneurons are increased in the cingulate cortex, retrosplenial granular cortex, and motor cortex. Interestingly, somatostatin (SST) positive and neuropeptide Y (NPY) interneurons are decreased in some brain regions, suggesting that DN-DISC1 expression affects the localization of interneuron subtypes. To further explore the cellular mechanisms that cause this change, DN-DISC1 suppresses proliferation and promotes the cell cycle exit of progenitors in the medial ganglionic eminence (MGE), whereas it stimulates ectopic proliferation of neighboring cells through cell non-autonomous effect. Mechanistically, it modulates GSK3 activity and interrupts Dlx2 activity in the Wnt activation. In sum, our results provide evidence that specific genetic insults on NSCs at a short period of time could lead to prolonged changes of brain metabolism and development, eventually behavioral defects.

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“…The accompanying paper from Rhee et al [69] focuses on a thorough analysis of the active and passive membrane properties of autaptic neurons, obtained by either classical differentiation or transcription factor-based forward programming, forcing the expression of NGN2 [68] or ASCL-1 and DLX2 into safe-harbor AAVS1 alleles [74,75] to generate glutamatergic or GABAergic forebrain neurons, respectively. Interestingly, the GABAergic neuronal population differentiated with this protocol includes different subtypes of GABAergic neurons, such as a high percentage of parvalbumin neurons and also calbindin and somatostatin subtypes, suggesting a higher level of the culture maturation compared to previous protocols.…”

Section: Improvements In 2d Culture: Single Cell Models To Study Synamentioning

confidence: 99%

Progress of Induced Pluripotent Stem Cell Technologies to Understand Genetic Epilepsy

Sterlini

Fruscione

Baldassari

et al. 2020

IJMS

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The study of the pathomechanisms by which gene mutations lead to neurological diseases has benefit from several cellular and animal models. Recently, induced Pluripotent Stem Cell (iPSC) technologies have made possible the access to human neurons to study nervous system disease-related mechanisms, and are at the forefront of the research into neurological diseases. In this review, we will focalize upon genetic epilepsy, and summarize the most recent studies in which iPSC-based technologies were used to gain insight on the molecular bases of epilepsies. Moreover, we discuss the latest advancements in epilepsy cell modeling. At the two dimensional (2D) level, single-cell models of iPSC-derived neurons lead to a mature neuronal phenotype, and now allow a reliable investigation of synaptic transmission and plasticity. In addition, functional characterization of cerebral organoids enlightens neuronal network dynamics in a three-dimensional (3D) structure. Finally, we discuss the use of iPSCs as the cutting-edge technology for cell therapy in epilepsy.

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Generation of pure GABAergic neurons by transcription factor programming

Cited by 277 publications

References 41 publications

Neuronal replacement therapy: previous achievements and challenges ahead

Neuronal replacement therapy: previous achievements and challenges ahead

A prenatal interruption of DISC1 function in the brain exhibits a lasting impact on adult behaviors, brain metabolism, and interneuron development

Progress of Induced Pluripotent Stem Cell Technologies to Understand Genetic Epilepsy

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