PT  - JOURNAL ARTICLE
AU  - Pascal Ender
AU  - Paolo Armando Gagliardi
AU  - Maciej Dobrzyński
AU  - Agne Frismantiene
AU  - Coralie Dessauges
AU  - Thomas Höhener
AU  - Marc-Antoine Jacques
AU  - Andrew R. Cohen
AU  - Olivier Pertz
TI  - Spatio-temporal Control of ERK Pulse Frequency Coordinates Fate Decisions during Mammary Acinar Morphogenesis
AID  - 10.1101/2020.11.20.387167
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2020.11.20.387167
4099  - http://biorxiv.org/content/early/2022/06/24/2020.11.20.387167.short
4100  - http://biorxiv.org/content/early/2022/06/24/2020.11.20.387167.full
AB  - The signaling events controlling proliferation, survival, and apoptosis during mammary epithelial acinar morphogenesis remain poorly characterized. By imaging single-cell ERK activity dynamics in MCF10A acini, we find that these fates depend on the average frequency of non-periodic ERK pulses. High pulse frequency is observed during initial acinus growth, correlating with rapid cell motility. Subsequent decrease in motility correlates with lower ERK pulse frequency and quiescence. Later, during lumen formation, coordinated ERK waves emerge across multiple cells of an acinus, correlating with high and low ERK pulse frequency in outer surviving and inner dying cells respectively. Optogenetic entrainment of ERK pulses causally connects high ERK pulse frequency with inner cell survival. Acini harboring the PIK3CA H1047R mutation, commonly observed in breast cancer, display increased ERK pulse frequency, inner cell survival and loss of lumen formation. Thus, fate decisions during acinar morphogenesis are fine-tuned by different spatio-temporal coordination modalities of ERK pulse frequency.Competing Interest StatementThe authors have declared no competing interest.