Evidence for evolutionary divergence of activity-dependent gene expression in developing neurons
- University of Edinburgh, United Kingdom
- UCL Institute of Neurology, United Kingdom
- MRC National Institute for Medical Research, United Kingdom
Abstract
Evolutionary differences in gene regulation between humans and lower mammalian experimental systems are incompletely understood, a potential translational obstacle that is challenging to surmount in neurons, where primary tissue availability is poor. Rodent-based studies show that activity-dependent transcriptional programs mediate myriad functions in neuronal development, but the extent of their conservation in human neurons is unknown. We compared activity-dependent transcriptional responses in developing human stem cell-derived cortical neurons with those induced in developing primary- or stem cell-derived mouse cortical neurons. While activity-dependent gene-responsiveness showed little dependence on developmental stage or origin (primary tissue vs. stem cell), notable species-dependent differences were observed. Moreover, differential species-specific gene ortholog regulation was recapitulated in aneuploid mouse neurons carrying human chromosome-21, implicating promoter/enhancer sequence divergence as a factor, including human-specific activity-responsive AP-1 sites. These findings support the use of human neuronal systems for probing transcriptional responses to physiological stimuli or indeed pharmaceutical agents.
Article and author information
Author details
Karolina Punovuori
Victor LJ Tybulewicz
Giles E Hardingham
Funding
Medical Research Council
- Giles E Hardingham
Wellcome
- Giles E Hardingham
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Anne West, Duke University School of Medicine, United States
Ethics
Animal experimentation: Animals used in this study were treated in accordance with UK Animal Scientific Procedures Act (1986) and the work subject to local ethical review approval by the University of Edinburgh Ethical Review Committee. The relevant project licence is 7009008, and the use of genetically modified organisms approved by local committee reference SBMS 13_007.
Version history
- Received: August 12, 2016
- Accepted: September 30, 2016
- Accepted Manuscript published: October 1, 2016 (version 1)
- Accepted Manuscript updated: October 12, 2016 (version 2)
- Version of Record published: November 2, 2016 (version 3)
- Version of Record updated: November 8, 2016 (version 4)
Copyright
© 2016, Qiu 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.
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Evidence for evolutionary divergence of activity-dependent gene expression in developing neurons
eLife 5:e20337.
https://doi.org/10.7554/eLife.20337
Further reading
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The emergence of new protein functions is crucial for the evolution of organisms. This process has been extensively researched for soluble enzymes, but it is largely unexplored for membrane transporters, even though the ability to acquire new nutrients from a changing environment requires evolvability of transport functions. Here, we demonstrate the importance of environmental pressure in obtaining a new activity or altering a promiscuous activity in members of the amino acid-polyamine-organocation (APC)-type yeast amino acid transporters family. We identify APC members that have broader substrate spectra than previously described. Using in vivo experimental evolution, we evolve two of these transporter genes, AGP1 and PUT4, toward new substrate specificities. Single mutations on these transporters are found to be sufficient for expanding the substrate range of the proteins, while retaining the capacity to transport all original substrates. Nonetheless, each adaptive mutation comes with a distinct effect on the fitness for each of the original substrates, illustrating a trade-off between the ancestral and evolved functions. Collectively, our findings reveal how substrate-adaptive mutations in membrane transporters contribute to fitness and provide insights into how organisms can use transporter evolution to explore new ecological niches.
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