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

Abstract

The adult mammalian brain contains an enormous variety of neuronal types, which are generally categorized in large groups, based on their neurochemical identity, hodological properties and molecular markers. This broad classification has allowed the correlation between individual neural progenitor populations and their neuronal progeny, thus contributing to probe the cellular and molecular mechanisms involved in neuronal identity determination during central nervous system (CNS) development. In this review, we discuss the contribution of the proneural genes Neurogenin2 (Neurog2) and Achaete-scute homolog 1 (Ascl1) for the specification of neuronal phenotypes in the developing neocortex, cerebellum and retina. Then, we revise recent data on astroglia cell lineage reprogramming into induced neurons using the same proneural proteins to compare the neuronal phenotypes obtained from astroglial cells originated in those CNS regions. We conclude that Ascl1 and Neurog2 have different contributions to determine neuronal fates, depending on the neural progenitor or astroglial population expressing those proneural factors. Finally, we discuss some possible explanations for these seemingly conflicting effects of Ascl1 and Neurog2 and propose future approaches to further dissect the molecular mechanisms of neuronal identity specification.

Evidence of Müller Glia Conversion Into Retina Ganglion Cells Using Neurogenin2

“…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 ).…”

Inhibition of Glioma Development by ASCL1-Mediated Direct Neuronal Reprogramming

“…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).…”

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

“…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 ).…”