Preprints Reviewed by eLife: A “tour-de-force” study of neuronal maturation

Read what peer reviewers thought about a recent preprint on chromatin accessibility and neuronal maturation.
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As readers may know, eLife only reviews papers that have been posted as preprints. As part of this process our reviewers write ‘public reviews’ that discuss the strengths and limitations of the preprint, and our editors synthesize these into a short ‘evaluation summary’ that encapsulates their views on the paper.

The evaluation summary and public reviews are posted alongside the preprint, and the authors can post a response to both if they wish. Authors are also sent additional detailed feedback on their preprint, including suggestions for improvement, and this feedback is posted alongside the article if it is accepted for publication in eLife.

Last month we highlighted three preprints that had been reviewed in this way. Below we highlight another preprint that has been reviewed by eLife.

Preprint title: Reorganization of postmitotic neuronal chromatin accessibility for maturation of serotonergic identity

In this bioRxiv preprint the authors explore the maturation process that neuronal transcriptomes undergo in order to acquire specialized neuronal identities. As part of this process various transcription factors must have access to certain regulatory sequences in neuronal chromatin. However, the mechanisms that control access to this chromatin – which is embedded in nucleosomes – are poorly understood. The authors use a range of techniques to explore how access to the chromatin is controlled.

Here is what the evaluation summary for the preprint said:

This paper will be of interest to developmental biologists who study the gene regulatory mechanisms necessary for induction and maintenance of postmitotic neuronal identity. The study generated a useful resource of genomic data and provided new insights into the dynamic regulation of accessible chromatin regions in post-mitotic serotonin (5-HT) neurons of the mouse hindbrain. This work proposes two transcription factors (Pet1, Lmx1b) as necessary for establishment and maintenance of accessible chromatin regions in serotonin (5-HT) neurons. The study is a major technical achievement but some of the central claims are not yet fully demonstrated.

The three reviewers discussed the strengths and weaknesses of the work in more detail in their public reviews. Reviewer #1 listed five major conclusions from the preprint and summarized the strengths as follows:

Technically, this is a tour-de-force effort. The study employs cutting-edge molecular, genetic and biochemical methods – in vivo – to study the molecular mechanisms underlying serotonergic neuron maturation in wild-type and conditional mouse mutants for Pet1 and Lmx1b. Essential controls are included and the authors provide all necessary information to help the reader understand how the analysis of all datasets was performed.

Reviewer #1 also pointed out that “The mechanistic details of how [the transcription factors] Pet1 and Lmx1b open chromatin remain elusive”. Reviewer #2 went into more detail about this, and also included five outstanding questions in their public review:

1) how is sustained expression of Pet1 and Lmx1b combined with additional mechanism to regulate dynamic chromatin landscapes and gene expression during serotonergic maturation?

2) Are Pet1 and Lmx1b TFs involved in subtype diversity of serotonergic neurons?

3) If so, how is broad Pet1 and Lmx1b expression translated into gene specific defects in 5HT neuron subtypes?

4) Is Pet1 and Lmx1b binding dynamic along postmitotic serotonergic development?

5) How do Pet1 and Lmx1b mediate repression of gene expression?

The evaluation summary and public reviews were posted on March 18, 2022.

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