Transcriptional regulation of neuronal identity

Abstract

Neuronal diversity is an intrinsic feature of the nervous system. Transcription factors (TFs) are key regulators in the establishment of different neuronal identities; how are the actions of different TFs coordinated to orchestrate this diversity? Are there common features shared among the different neuron types of an organism or even among different animal groups? In this review, we provide a brief overview on common traits emerging on the transcriptional regulation of neuron type diversification with a special focus on the comparison between mouse and Caenorhabditis elegans model systems. In the first part, we describe general concepts on neuronal identity and transcriptional regulation of gene expression. In the second part of the review, TFs are classified in different categories according to their key roles at specific steps along the protracted process of neuronal specification and differentiation. The same TF categories can be identified both in mammals and nematodes. Importantly, TFs are very pleiotropic: Depending on the neuron type or the time in development, the same TF can fulfil functions belonging to different categories. Finally, we describe the key role of transcriptional repression at all steps controlling neuronal diversity and propose that acquisition of neuronal identities could be considered a metastable process.

Keywords: enhancer; neuronal differentiation; neuronal identity; regulation of gene expression; regulatory genome; repression; transcription factor.

FIGURE 1

Basic concepts on transcriptional regulation of gene expression. (a) The complete expression pattern of each gene is the result of the combined action of several enhancer modules. This modularity allows for spatial and temporal segregation of enhancer function, as well as redundancy (shadow enhancers) and robustness of gene expression. (b) Transcription factors act in a combinatorial fashion on enhancers. Combinatorial actions of TFs allow for (1) pleiotropic functions. In the example, the TF represented as a blue triangle is expressed both in Neuron types A and B but activates different target genes because it works with cell type specific combination of TFs. (2) Increase enhancer specificity, as only regions with the complete collection of TF binding motifs will act as enhancers. (3) Robustness of gene expression, as the lack of a TF or a TF binding motif can be sometimes buffered by the rest of TFs. (4) Flexibility, because an enhancer can usually accommodate very flexible dispositions of TF binding motifs without losing activity. (5) Developmental fingerprint: An enhancer can be bound by different collections of TFs at different times in development; TF binding motifs present in the enhancer are a fingerprint of TF activities on enhancers at different developmental times

FIGURE 2

Main regulatory steps in the establishment of specific neuronal identities. Different concentrations of morphogens differentially modulate the activity of signal regulated TFs that in turn activate expression of specific spatial/lineage TFs and proneural factors. In Drosophila, the temporal progression of progenitors is delineated by the serial expression of temporal TFs that increases diversity of generated neuron types. These TF categories work together to control progenitor proliferation, to induce expression of downstream TFs, to impose specific genomic architectures and to avoid expression of alternative neuronal fates. Both activation and repression are combined to achieve the actions of this set of TFs. Postmitotic differentiating neurons combine transient processes of gene activation that control migration, morphological maturation, axon guidance and synaptic connectivity with the regulation of stable gene expression to induce terminal differentiation and functional maturation. Terminal selectors, transiently expressed TFs and activity/signal regulated TFs work together in these different steps. Again, both repression and activation of gene expression are required for correct neuronal differentiation