Evidence for evolutionary divergence of activity-dependent gene expression in developing neurons.
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.
School of Biomedical Sciences, University of Edinburgh, Edinburgh, United Kingdom.
Jing
J
Qiu
School of Biomedical Sciences, University of Edinburgh, Edinburgh, United Kingdom.
Jamie
J
McQueen
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom.
Bilada
B
Bilican
School of Biomedical Sciences, University of Edinburgh, Edinburgh, United Kingdom.|Centre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative Medicine, National Centre for Biological Sciences, Bangalore, India.
Owen
O
Dando
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom.
Dario
D
Magnani
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom.
Karolina
0000-0003-0297-1225
K
Punovuori
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom.
Bhuvaneish T
BT
Selvaraj
School of Biomedical Sciences, University of Edinburgh, Edinburgh, United Kingdom.
Matthew
M
Livesey
School of Biomedical Sciences, University of Edinburgh, Edinburgh, United Kingdom.|MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom.
Ghazal
G
Haghi
School of Informatics, University of Edinburgh, Edinburgh, United Kingdom.
Samuel
S
Heron
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom.
Karen
K
Burr
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom.
Rickie
R
Patani
School of Biomedical Sciences, University of Edinburgh, Edinburgh, United Kingdom.|MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom.
Rinku
R
Rajan
Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom.
Olivia
O
Sheppard
School of Biomedical Sciences, University of Edinburgh, Edinburgh, United Kingdom.|Centre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative Medicine, National Centre for Biological Sciences, Bangalore, India.
Peter C
PC
Kind
School of Informatics, University of Edinburgh, Edinburgh, United Kingdom.
T Ian
0000-0003-0495-7187
TI
Simpson
The Francis Crick Institute, London, United Kingdom.|Imperial College, London, United Kingdom.
Victor Lj
0000-0003-2439-0798
VL
Tybulewicz
School of Biomedical Sciences, University of Edinburgh, Edinburgh, United Kingdom.
David Ja
0000-0002-4957-6049
DJ
Wyllie
Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom.
Elizabeth Mc
EM
Fisher
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom.
Sally
0000-0002-4018-9480
S
Lowell
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom.|Centre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative Medicine, National Centre for Biological Sciences, Bangalore, India.
Siddharthan
S
Chandran
School of Biomedical Sciences, University of Edinburgh, Edinburgh, United Kingdom.
Giles E
0000-0002-7629-5314
GE
Hardingham
D000818:Animals; D005075:Biological Evolution; D002478:Cells, Cultured; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D058953:Neural Stem Cells / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D014158:Transcription, Genetic
calcium signaling; evolutionary biology; gene expression; genomics; human; mouse; neuronal activity; neuroscience; transcription
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