Downregulation of ribosome biogenesis during early forebrain development
- Boston Children's Hospital, United States
Abstract
Forebrain precursor cells are dynamic during early brain development, yet the underlying molecular changes remain elusive. We observed major differences in transcriptional signatures of precursor cells from mouse forebrain at embryonic days E8.5 vs. E10.5 (before vs. after neural tube closure). Genes encoding protein biosynthetic machinery were strongly downregulated at E10.5. This was matched by decreases in ribosome biogenesis and protein synthesis, together with age-related changes in proteomic content of the adjacent fluids. Notably, c-MYC expression and mTOR pathway signaling were also decreased at E10.5, providing a potential driver for the effects on ribosome biogenesis and protein synthesis. Interference with c-MYC at E8.5 prematurely decreased ribosome biogenesis, while persistent c-MYC expression in cortical progenitors increased transcription of protein biosynthetic machinery and enhanced ribosome biogenesis, as well as enhanced progenitor proliferation leading to subsequent macrocephaly. These findings indicate large, coordinated changes in molecular machinery of forebrain precursors during early brain development.
Data availability
Sequencing data have been deposited in GEO under accession number GSE100421.
Article and author information
Author details
Funding
National Science Foundation (Graduate Research Fellowship)
- Kevin F Chau
National Institutes of Health (R01 NS088566)
- Maria K Lehtinen
Pediatric Hydrocephalus Foundation (Research grant)
- Maria K Lehtinen
Simons Foundation (SFARI Pilot Grant)
- Maria K Lehtinen
New York Stem Cell Foundation (Robertson Investigator)
- Maria K Lehtinen
National Institutes of Health (NIH T32 HL110852)
- Kevin F Chau
National Institutes of Health (NIH T32 HL110852)
- Ryann M Fame
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Marianne Bronner, California Institute of Technology, United States
Ethics
Animal experimentation: All animal experimentation was carried out under protocols approved by the IACUC of Boston Children's Hospital (protocol number 17-10-3547R).
Version history
- Received: March 28, 2018
- Accepted: May 9, 2018
- Accepted Manuscript published: May 10, 2018 (version 1)
- Version of Record published: June 1, 2018 (version 2)
Copyright
© 2018, Chau et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 5,380
- views
-
- 754
- downloads
-
- 73
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
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)
Downregulation of ribosome biogenesis during early forebrain development
eLife 7:e36998.
https://doi.org/10.7554/eLife.36998
Further reading
-
- Immunology and Inflammation
- Neuroscience
CD4+CD25+Foxp3+ regulatory T cells (Treg) have been implicated in pain modulation in various inflammatory conditions. However, whether Treg cells hamper pain at steady state and by which mechanism is still unclear. From a meta-analysis of the transcriptomes of murine Treg and conventional T cells (Tconv), we observe that the proenkephalin gene (Penk), encoding the precursor of analgesic opioid peptides, ranks among the top 25 genes most enriched in Treg cells. We then present various evidence suggesting that Penk is regulated in part by members of the Tumor Necrosis Factor Receptor (TNFR) family and the transcription factor Basic leucine zipper transcription faatf-like (BATF). Using mice in which the promoter activity of Penk can be tracked with a fluorescent reporter, we also show that Penk expression is mostly detected in Treg and activated Tconv in non-inflammatory conditions in the colon and skin. Functionally, Treg cells proficient or deficient for Penk suppress equally well the proliferation of effector T cells in vitro and autoimmune colitis in vivo. In contrast, inducible ablation of Penk in Treg leads to heat hyperalgesia in both male and female mice. Overall, our results indicate that Treg might play a key role at modulating basal somatic sensitivity in mice through the production of analgesic opioid peptides.
-
- Neuroscience
Biological synaptic transmission is unreliable, and this unreliability likely degrades neural circuit performance. While there are biophysical mechanisms that can increase reliability, for instance by increasing vesicle release probability, these mechanisms cost energy. We examined four such mechanisms along with the associated scaling of the energetic costs. We then embedded these energetic costs for reliability in artificial neural networks (ANNs) with trainable stochastic synapses, and trained these networks on standard image classification tasks. The resulting networks revealed a tradeoff between circuit performance and the energetic cost of synaptic reliability. Additionally, the optimised networks exhibited two testable predictions consistent with pre-existing experimental data. Specifically, synapses with lower variability tended to have (1) higher input firing rates and (2) lower learning rates. Surprisingly, these predictions also arise when synapse statistics are inferred through Bayesian inference. Indeed, we were able to find a formal, theoretical link between the performance-reliability cost tradeoff and Bayesian inference. This connection suggests two incompatible possibilities: evolution may have chanced upon a scheme for implementing Bayesian inference by optimising energy efficiency, or alternatively, energy-efficient synapses may display signatures of Bayesian inference without actually using Bayes to reason about uncertainty.
