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

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Gene regulation differences between humans and rodents hinder neurological research.
• Activity-dependent transcriptional programs are crucial for neuronal development but their conservation in humans is unclear.
• Limited availability of human neuronal tissue complicates studies.

Purpose of the Study:

• To compare activity-dependent transcriptional responses in human and mouse neurons.
• To investigate the conservation of neuronal gene regulation across species.
• To identify factors contributing to species-specific gene regulation.

Main Methods:

• Comparison of activity-dependent transcriptional responses in human stem cell-derived cortical neurons and mouse cortical neurons (primary and stem cell-derived).
• Analysis of gene ortholog regulation in aneuploid mouse neurons carrying human chromosome-21.
• Investigation of promoter/enhancer sequence divergence, including AP-1 sites.

Main Results:

• Activity-dependent gene responsiveness was largely conserved across developmental stages and cell origins (primary vs. stem cell).
• Significant species-dependent differences in gene regulation were observed between human and mouse neurons.
• Differential gene ortholog regulation was recapitulated in aneuploid mouse neurons, suggesting sequence divergence is a key factor.

Conclusions:

• Human and mouse neurons exhibit distinct activity-dependent gene regulation.
• Sequence divergence, including human-specific AP-1 sites, contributes to these species-specific differences.
• Human neuronal systems are valuable for studying transcriptional responses to stimuli and drugs.