Evidence for evolutionary divergence of activity-dependent gene expression in developing neurons

Jing Qiu, Jamie McQueen, Bilada Bilican, Owen Dando, Dario Magnani, Karolina Punovuori, Bhuvaneish T Selvaraj, Matthew Livesey, Ghazal Haghi, Sam Heron, Karen Burr, Rickie Patani, Rinku Rajan, Olivia Sheppard, Peter C Kind, T. Ian Simpson, Victor LJ Tybulewicz, David JA Wyllie, Elizabeth MC Fisher, Sally LowellSiddharthan Chandran, Giles E Hardingham

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.
Original languageEnglish
Article numbere20337
Number of pages15
JournaleLIFE
Volume5
Early online date1 Oct 2016
DOIs
Publication statusPublished - 2 Nov 2016

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