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

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posted on 14.09.2020 by Jing Qiu, Jamie McQueen, Bilada Bilican, Owen Dando, Dario Magnani, Karolina Punovuori, Bhuvaneish T Selvaraj, Matthew Livesey, Ghazal Haghi, Samuel 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 Lowell, Siddharthan Chandran, Giles E Hardingham
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.

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