Mechanisms regulating GABAergic neuron development

Abstract

Neurons using gamma-aminobutyric acid (GABA) as their neurotransmitter are the main inhibitory neurons in the mature central nervous system (CNS) and show great variation in their form and function. GABAergic neurons are produced in all of the main domains of the CNS, where they develop from discrete regions of the neuroepithelium. Here, we review the gene expression and regulatory mechanisms controlling the main steps of GABAergic neuron development: early patterning of the proliferative neuroepithelium, production of postmitotic neural precursors, establishment of their identity and migration. By comparing the molecular regulation of these events across CNS, we broadly identify three regions utilizing distinct molecular toolkits for GABAergic fate determination: telencephalon-anterior diencephalon (DLX2 type), posterior diencephalon-midbrain (GATA2 type) and hindbrain-spinal cord (PTF1A and TAL1 types). Similarities and differences in the molecular regulatory mechanisms reveal the core determinants of a GABAergic neuron as well as provide insights into generation of the vast diversity of these neurons.

Direct neuronal reprogramming: learning from and for development

“…For instance, expression of Ascl1 in cerebral cortex-derived astrocytes induces a GABAergic programme (Masserdotti et al, 2015), whereas it leads to the production of both GABAergic and glutamatergic neurons in dorsal midbrain astrocytes in vitro, consistent with its role during embryonic development in that region Achim et al, 2014). Interestingly, the efficiency of neuronal conversion is lower when instructing a type of neuron not normally generated from cells of this region.…”

“…In terms of their developmental origins, fibroblasts are more distantly related to neurons than are astrocytes, and so an important question is whether and how this affects direct reprogramming. glutamatergic neurons (Chanda et al, 2014), whereas it induces a mix of glutamatergic and GABAergic neurons from midbrain astrocytes (Achim et al, 2014;Liu et al, 2015). Likewise, fibroblasts transduced with Neurog2 and treated with small molecules (see next section) do not turn into glutamatergic neurons but rather acquire a cholinergic/motor neuron identity (Liu et al, 2013).…”

“…Rather than recapitulating the exact developmental signalling environment required for the activation of specific transcription factor networks (Achim et al, 2014;Briscoe and Small, 2015), a more direct approach to neuronal subtype specification could be to overexpress the respective transcriptional regulators of a core specification programme active during development. Indeed, this approach has been used for inducing many other neuronal subtypes lost in traumatic injury or neurodegenerative diseases, and generation of which in vitro could be potentially useful for cellbased therapies as well as for disease modelling (Blanchard et al, 2015;Caiazzo et al, 2011;Gascón et al, 2016;Rouaux and Arlotta, 2013;Son et al, 2011;Victor et al, 2014;Wainger et al, 2015).…”

“…1B). Likewise, GABAergic neurons are specified by Dlx genes in the ventral telencephalon (Casarosa et al, 1999;Guillemot et al, 1993;Poitras et al, 2007), by Gata2 and Helt (also known as Megane) in the di-and mesencephalon, and by Ptf1a in the spinal cord, cerebellum and retina (Achim et al, 2014). In the dorsal midbrain, the generation of GABAergic neurons requires the expression of Ascl1 and Helt (Guimera et al, 2006;Wende et al, 2015).…”

Epigenetic Regulations of GABAergic Neurotransmission: Relevance for Neurological Disorders and Epigenetic Therapy

“…The GABAergic neuron formation from neuroepithelial GABAergic progenitor populations and GABA fate determination (excitatory vs. inhibitory) occur in all compartments of the neural tube: forebrain (telencephalon and diencephalon), midbrain and hindbrain (fig. 2) [42,43]. Achim et al [42] comprehensively reviewed the regulation of GABAergic neurogenesis across the CNS (telencephalon-anterior diencephalon, posterior diencephalon-midbrain and hindbrain-spinal cord); their article discusses the discrete gene expression patterns and transcription factor activation in different brain regions controlling the GABAergic neurons and signaling.…”