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Review
. 2022 Jan 11;17(1):14-34.
doi: 10.1016/j.stemcr.2021.11.015. Epub 2021 Dec 30.

Making neurons, made easy: The use of Neurogenin-2 in neuronal differentiation

Amy J Hulme  1 , Simon Maksour  1 , Mitchell St-Clair Glover  1 , Sara Miellet  1 , Mirella Dottori  2
Affiliations
Review

Making neurons, made easy: The use of Neurogenin-2 in neuronal differentiation

Amy J Hulme et al. Stem Cell Reports. .

Abstract

Directed neuronal differentiation of human pluripotent stem cells (hPSCs), neural progenitors, or fibroblasts using transcription factors has allowed for the rapid and highly reproducible differentiation of mature and functional neurons. Exogenous expression of the transcription factor Neurogenin-2 (NGN2) has been widely used to generate different populations of neurons, which have been used in neurodevelopment studies, disease modeling, drug screening, and neuronal replacement therapies. Could NGN2 be a "one-glove-fits-all" approach for neuronal differentiations? This review summarizes the cellular roles of NGN2 and describes the applications and limitations of using NGN2 for the rapid and directed differentiation of neurons.

Keywords: NGN2; Neurogenin-2; induced neurons; neural differentiation; neural progenitors; pluripotent stem cells; transcription factor.

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Conflict of interest statement

Conflicts of interest The authors have no financial interests to declare.

Figures

None
Graphical abstract
Figure 1
Figure 1
Summary of the role NGN2 plays in the differentiation of different neuronal subtypes During the differentiation of glutamatergic cortical neurons, PAX6 activates NGN2, which in turn inhibits PAX6 and results in the activation of the cortical transcription factor cascade (orange pathway). NGN2 is phosphorylated at two serine residue sites and forms a complex with LHX3 and ISLET1, activating genes required for motor neuron differentiation (green pathway). NGN2 plays a role in dopaminergic neuron differentiation but is not a critical regulator (purple pathway). NGN2 plays a role in the waves of sensory neurogenesis, in turn activating the genes required for differentiation of specific peripheral sensory neuron subtypes (pink pathway). NGN2 inhibits MASH1, a transcription factor required for GABAergic neuron generation (gray pathway). WNT signaling activates NGN2, which represses the differentiation of astrocytes and oligodendrocytes by the downregulation of astrocyte genes and OLIG2, respectively (cream pathway).
Figure 2
Figure 2
Summary of the applications of NGN2 iNs (A and B). NGN2 overexpression in the differentiation of neurons has been applied to development (A) and disease modeling of various neurodegenerative and neuropsychiatric diseases in vitro (B). (C). Reduced differentiation time and scalability of iNs have allowed NGN2 iNs to be applied for high-throughput compound screening (C). (D). Following injury to the central nervous system, NGN2 overexpression has been applied to convert glial cells to neurons for neuronal replacement therapies (D).
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