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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.

SUBMITTER: Sousa E

PROVIDER: S-EPMC9306894 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Normal differentiation and induced reprogramming require the activation of target cell programs and silencing of donor cell programs. In reprogramming, the same factors are often used to reprogram many different donor cell types. As most developmental repressors, such as RE1-silencing transcription factor (REST) and Groucho (also known as TLE), are considered lineage-specific repressors, it remains unclear how identical combinations of transcription factors can silence so many different donor programs. Distinct lineage repressors would have to be induced in different donor cell types. Here, by studying the reprogramming of mouse fibroblasts to neurons, we found that the pan neuron-specific transcription factor Myt1-like (Myt1l) exerts its pro-neuronal function by direct repression of many different somatic lineage programs except the neuronal program. The repressive function of Myt1l is mediated via recruitment of a complex containing Sin3b by binding to a previously uncharacterized N-terminal domain. In agreement with its repressive function, the genomic binding sites of Myt1l are similar in neurons and fibroblasts and are preferentially in an open chromatin configuration. The Notch signalling pathway is repressed by Myt1l through silencing of several members, including Hes1. Acute knockdown of Myt1l in the developing mouse brain mimicked a Notch gain-of-function phenotype, suggesting that Myt1l allows newborn neurons to escape Notch activation during normal development. Depletion of Myt1l in primary postmitotic neurons de-repressed non-neuronal programs and impaired neuronal gene expression and function, indicating that many somatic lineage programs are actively and persistently repressed by Myt1l to maintain neuronal identity. It is now tempting to speculate that similar 'many-but-one' lineage repressors exist for other cell fates; such repressors, in combination with lineage-specific activators, would be prime candidates for use in reprogramming additional cell types.

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Transcriptional regulation of neuronal identity.

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