Neurogenesis: Give it a REST!
To construct the mammalian brain, the right neurons must be produced in the right place at the right time. For example, the outer layer of the brain, the cortex, consists of six layers of neurons and is built up one layer at a time. This is achieved by controlling how cells called apical progenitors become basal progenitors, which then specialize into new neurons (Gotz et al., 2002; Figure 1). If the apical progenitors become basal progenitors too soon, several developmental brain abnormalities can result, the brain may be too small (a condition known as microcephaly), or the layering of the cortex may be disrupted. Now, in eLife, Gail Mandel of the Oregon Health and Science University and co-workers – including Tamilla Neichiporuk as first author – report that a protein called REST has an unexpected role in protecting the genome of these progenitor cells (Nechiporuk et al., 2016).

REST regulation in embryonic neurogenesis.
The REST protein is expressed in apical progenitors (green cells) and represses the expression of genes that are necessary for neurons (pink cell) to develop. Left: REST maintains genome stability, protecting the DNA of the apical progenitor cell during S phase (the phases of the cell cycle are shown in the yellow and white oval). The cells then reduce the production of REST precisely at the apical progenitor cell cycle exit (during G1 phase). This ensures that new neurons develop properly. Right: In the absence of REST, the DNA of the apical progenitor cell becomes damaged during S phase, preventing the subsequent production of basal progenitors and neurons.
The identity of a cell is determined to a large extent by which of its genes are transcribed. Therefore, when a new neuron first develops from a progenitor cell, a process of 'transcriptional resetting' must occur so that the genes that need to be expressed in mature neurons can be activated. The REST protein, first identified in 1995, is expressed in all cells except for mature neurons, and so researchers immediately suspected that it was involved in repressing neuronal genes (Schoenherr and Anderson, 1995; Chen et al., 1998; Bruce et al., 2004).
Support for this idea came from experiments that showed that REST binds to and represses genetic elements that are associated with many genes that are specific to mature neurons. As part of this repression, REST recruits a series of repressor complexes that alter how the gene is packed into a structure called chromatin. However, a previous study involving knockout mice who could not produce the REST protein failed to identify any significant abnormalities in the developing or adult brain (Gao et al., 2011; Aoki et al., 2012: Yang et al, 2012). The role of REST has therefore remained uncertain.
Nechiporuk et al. – who are based in the US and Germany – have now used a technique called conditional genetic ablation to explore the role of REST in neural progenitors. This revealed an unexpected requirement for REST in protecting the genome of the apical progenitors. Loss of REST induces DNA damage during the S phase of the cell cycle: this is the phase during which DNA is replicated. A consequence of this damage is the acquisition of chromosomal abnormalities in the apical progenitors. This triggers cells to commit suicide – following the orders of a protein called p53 – and the result is microcephaly. Nechiporuk et al. also show that the combined loss of REST and p53 results in the formation of a highly aggressive brain tumour called a glioblastoma. REST therefore performs a dual role during brain development: it protects the progenitor cells from genetic catastrophe, and it silences neuronal gene expression until the time is right.
These findings came as a surprise, given the results of the previous REST knockout studies. However, in a series of elegant experiments Nechiporuk et al. showed that these earlier mouse models did not fully delete the REST coding sequences: the knockout mice still produced a C-terminal peptide that was able to recruit the repressor complexes that helped to silence certain genes. This is a valuable lesson for all researchers – knocking out a gene does not always result in a complete loss of function.
Why does the premature removal of the repressor complexes recruited by REST inflict widespread genomic damage? One possibility proposed by Nechiporuk et al. is that the associated loss of chromatin repression might lead to a subset of neuronal genes being incorrectly transcribed. Thus, REST seems to provide a ‘license’ for progenitors to transform into their final neuronal form by guarding the genome and preventing the premature transcription of genes specific to mature neurons. These new findings address a question that has received little attention to date – how are genome maintenance and transcriptional control coordinated as new neurons develop from progenitor cells?
As with all interesting discoveries, many new questions arise: how is REST protecting neuronal gene integrity during S-phase? How are the processes of cell cycle exit, chromatin repression, and the DNA replication timing coordinated during the birth of new neurons? New insights into how REST orchestrates gene regulation during the construction of the nervous system will clearly enhance our understanding of diseases such as microcephaly and brain cancer. It seems that for neural progenitors, a little REST is what it takes to ensure you reach your full potential!
References
-
Genome-wide analysis of repressor element 1 silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF) target genesProceedings of the National Academy of Sciences USA 101:10458–10463.https://doi.org/10.1073/pnas.0401827101
-
The cell biology of neurogenesisNature Reviews Molecular Cell Biology 6:777–788.https://doi.org/10.1038/nrm1739
Article and author information
Author details
Publication history
Copyright
© 2016, Pollard et al.
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,831
- views
-
- 185
- downloads
-
- 2
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Developmental Biology
- Stem Cells and Regenerative Medicine
In holothurians, the regenerative process following evisceration involves the development of a ‘rudiment’ or ‘anlage’ at the injured end of the mesentery. This regenerating anlage plays a pivotal role in the formation of a new intestine. Despite its significance, our understanding of the molecular characteristics inherent to the constituent cells of this structure has remained limited. To address this gap, we employed state-of-the-art scRNA-seq and hybridization chain reaction fluorescent in situ hybridization analyses to discern the distinct cellular populations associated with the regeneration anlage. Through this approach, we successfully identified 13 distinct cell clusters. Among these, two clusters exhibit characteristics consistent with putative mesenchymal cells, while another four show features akin to coelomocyte cell populations. The remaining seven cell clusters collectively form a large group encompassing the coelomic epithelium of the regenerating anlage and mesentery. Within this large group of clusters, we recognized previously documented cell populations such as muscle precursors, neuroepithelial cells, and actively proliferating cells. Strikingly, our analysis provides data for identifying at least four other cellular populations that we define as the precursor cells of the growing anlage. Consequently, our findings strengthen the hypothesis that the coelomic epithelium of the anlage is a pluripotent tissue that gives rise to diverse cell types of the regenerating intestinal organ. Moreover, our results provide the initial view into the transcriptomic analysis of cell populations responsible for the amazing regenerative capabilities of echinoderms.
-
- Cell Biology
- Developmental Biology
Long thought to have little relevance to ovarian physiology, the rete ovarii may have a role in follicular dynamics and reproductive health.