Instructing neuronal identity during CNS development and astroglial-lineage reprogramming: Roles of NEUROG2 and ASCL1

Chouchane, Malek; Costa, Marcos Romualdo

doi:10.1016/j.brainres.2018.02.045

Cited by 20 publications

(16 citation statements)

References 99 publications

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“…Recent work in our laboratory has shown that the origin of astroglial cells, either from cerebral cortex or cerebellum, affects the phenotype of iNs lineage-converted by either ASCL1 or NEUROG2 (Chouchane et al, 2017 ). Notably, most iNs generated from astroglia from either cerebellum or neocortex showed central hallmarks of neurons commonly observed in those regions, suggesting that a “molecular memory” in the astroglial cells contributes to the acquisition of specific neuronal phenotypes in iNs (Chouchane and Costa, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Evidence of Müller Glia Conversion Into Retina Ganglion Cells Using Neurogenin2

Guimarães

Landeira

Coelho

et al. 2018

Front. Cell. Neurosci.

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Degenerative retinopathies are the leading causes of irreversible visual impairment in the elderly, affecting hundreds of millions of patients. Müller glia cells (MGC), the main type of glia found in the vertebrate retina, can resume proliferation in the rodent adult injured retina but contribute weakly to tissue repair when compared to zebrafish retina. However, postnatal and adult mouse MGC can be genetically reprogrammed through the expression of the transcription factor (TF) Achaete-scute homolog 1 (ASCL1) into induced neurons (iNs), displaying key hallmarks of photoreceptors, bipolar and amacrine cells, which may contribute to regenerate the damaged retina. Here, we show that the TF neurogenin 2 (NEUROG2) is also sufficient to lineage-reprogram postnatal mouse MGC into iNs. The efficiency of MGC lineage conversion by NEUROG2 is similar to that observed after expression of ASCL1 and both TFs induce the generation of functionally active iNs. Treatment of MGC cultures with EGF and FGF2 prior to Neurog2 or Ascl1 expression enhances reprogramming efficiencies, what can be at least partially explained by an increase in the frequency of MGCs expressing sex determining region Y (SRY)-box 2 (SOX2). Transduction of either Neurog2 or Ascl1 led to the upregulation of key retina neuronal genes in MGC-derived iNs, but only NEUROG2 induced a consistent increase in the expression of putative retinal ganglion cell (RGC) genes. Moreover, in vivo electroporation of Neurog2 in late progenitors from the neonatal rat retina, which are transcriptionally similar to MGCs, also induced a shift in the generation of retinal cell subtypes, favoring neuronal differentiation at the expense of MGCs and resuming the generation of RGCs. Altogether, our data indicate that NEUROG2 induces lineage conversion of postnatal rodent MGCs into RGC-like iNs in vitro and resumes the generation of this neuronal type from late progenitors of the retina in vivo.

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Section: Discussionmentioning

confidence: 99%

Evidence of Müller Glia Conversion Into Retina Ganglion Cells Using Neurogenin2

Guimarães

Landeira

Coelho

et al. 2018

Front. Cell. Neurosci.

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“…During CNS development, ASCL1 is expressed in progenitor cells committed to the generation of GABAergic interneurons [42,43]. For lineage reprogramming, ASCL1 converts astrocytes from different origins into neurons adopting mostly a GABAergic phenotype or a mix of glutamatergic and GABAergic phenotypes [29,43,44,45]. Therefore, immunocytochemical analysis was performed to examine the subtype of glioma cell-converted neurons using specific markers, including vGluT1 (excitatory interneuron marker), GABA (inhibitory interneuron marker) and ChAT (motor neuron marker).…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Glioma Development by ASCL1-Mediated Direct Neuronal Reprogramming

Cheng

Tan

Huang

et al. 2019

Cells

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Direct conversion of non-neural cells into induced neurons holds great promise for brain repair. As the most common malignant tumor in the central nervous system, glioma is currently incurable due to its exponential growth and invasive behavior. Given that neurons are irreversible postmitotic cells, reprogramming glioma cells into terminally differentiated neuron-like cells represents a potential approach to inhibit brain tumor development. We here show that human glioma cells can be directly, rapidly and efficiently reprogrammed into terminally differentiated neuron-like cells by the single transcription factor ASCL1 (Achaete-scute complex-like 1, also known as MASH1). These induced cells exhibit typical neuron-like morphology and express multiple neuron-specific markers. Importantly, ASCL1-mediated neuronal reprogramming drives human glioma cells to exit the cell cycle and results in dramatic inhibition of proliferation, both in vitro and in vivo. Taken together, this proof-of-principle study demonstrates a potential strategy for impeding brain tumor development by ASCL1-induced direct neuronal reprogramming.

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“…Progenitors in the cerebellum and spinal cord express Neurog2 generate GABAergic and cholinergic neurons, respectively (Bertrand et al, 2002 ). Similarly, progenitors expressing Ascl1 contribute to different neuronal lineages in the cerebral cortex, cerebellum, and retina (Chouchane and Costa, 2018 ). Most protocols aiming at obtaining fibroblast-derived iNs with a particular phenotype through direct lineage reprogramming require the use of several TFs (Victor et al, 2014 ; Blanchard et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Direct Reprogramming of Adult Human Somatic Stem Cells Into Functional Neurons Using Sox2, Ascl1, and Neurog2

Araújo

Hilscher

Marques‐Coelho

et al. 2018

Front. Cell. Neurosci.

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Reprogramming of somatic cells into induced pluripotent stem cells (iPS) or directly into cells from a different lineage, including neurons, has revolutionized research in regenerative medicine in recent years. Mesenchymal stem cells are good candidates for lineage reprogramming and autologous transplantation, since they can be easily isolated from accessible sources in adult humans, such as bone marrow and dental tissues. Here, we demonstrate that expression of the transcription factors (TFs) SRY (sex determining region Y)-box 2 (Sox2), Mammalian achaete-scute homolog 1 (Ascl1), or Neurogenin 2 (Neurog2) is sufficient for reprogramming human umbilical cord mesenchymal stem cells (hUCMSC) into induced neurons (iNs). Furthermore, the combination of Sox2/Ascl1 or Sox2/Neurog2 is sufficient to reprogram up to 50% of transfected hUCMSCs into iNs showing electrical properties of mature neurons and establishing synaptic contacts with co-culture primary neurons. Finally, we show evidence supporting the notion that different combinations of TFs (Sox2/Ascl1 and Sox2/Neurog2) may induce multiple and overlapping neuronal phenotypes in lineage-reprogrammed iNs, suggesting that neuronal fate is determined by a combination of signals involving the TFs used for reprogramming but also the internal state of the converted cell. Altogether, the data presented here contribute to the advancement of techniques aiming at obtaining specific neuronal phenotypes from lineage-converted human somatic cells to treat neurological disorders.

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Instructing neuronal identity during CNS development and astroglial-lineage reprogramming: Roles of NEUROG2 and ASCL1

Cited by 20 publications

References 99 publications

Evidence of Müller Glia Conversion Into Retina Ganglion Cells Using Neurogenin2

Evidence of Müller Glia Conversion Into Retina Ganglion Cells Using Neurogenin2

Inhibition of Glioma Development by ASCL1-Mediated Direct Neuronal Reprogramming

Direct Reprogramming of Adult Human Somatic Stem Cells Into Functional Neurons Using Sox2, Ascl1, and Neurog2

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