@article{Hiratsuka:2020:10.1073/pnas.2006965117,
author = {Hiratsuka, T and Bordeu, I and Pruessner, G and Watt, FM},
doi = {10.1073/pnas.2006965117},
journal = {Proceedings of the National Academy of Sciences of USA},
pages = {17796--17807},
title = {Regulation of ERK basal and pulsatile activity control proliferation and exit from the stem cell compartment in mammalian epidermis.},
url = {http://dx.doi.org/10.1073/pnas.2006965117},
volume = {117},
year = {2020}
}

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TY  - JOUR
AB  - Fluctuation in signal transduction pathways is frequently observed during mammalian development. However, its role in regulating stem cells has not been explored. Here we tracked spatiotemporal ERK MAPK dynamics in human epidermal stem cells. While stem cells and differentiated cells were distinguished by high and low stable basal ERK activity, respectively, we also found cells with pulsatile ERK activity. Transitions from Basalhi-Pulselo (stem) to Basalhi-Pulsehi, Basalmid-Pulsehi, and Basallo-Pulselo (differentiated) cells occurred in expanding keratinocyte colonies and in response to differentiation stimuli. Pharmacological inhibition of ERK induced differentiation only when cells were in the Basalmid-Pulsehi state. Basal ERK activity and pulses were differentially regulated by DUSP10 and DUSP6, leading us to speculate that DUSP6-mediated ERK pulse down-regulation promotes initiation of differentiation, whereas DUSP10-mediated down-regulation of mean ERK activity promotes and stabilizes postcommitment differentiation. Levels of MAPK1/MAPK3 transcripts correlated with DUSP6 and DUSP10 transcripts in individual cells, suggesting that ERK activity is negatively regulated by transcriptional and posttranslational mechanisms. When cells were cultured on a topography that mimics the epidermal-dermal interface, spatial segregation of mean ERK activity and pulses was observed. In vivo imaging of mouse epidermis revealed a patterned distribution of basal cells with pulsatile ERK activity, and down-regulation was linked to the onset of differentiation. Our findings demonstrate that ERK MAPK signal fluctuations link kinase activity to stem cell dynamics.
AU  - Hiratsuka,T
AU  - Bordeu,I
AU  - Pruessner,G
AU  - Watt,FM
DO  - 10.1073/pnas.2006965117
EP  - 17807
PY  - 2020///
SN  - 0027-8424
SP  - 17796
TI  - Regulation of ERK basal and pulsatile activity control proliferation and exit from the stem cell compartment in mammalian epidermis.
T2  - Proceedings of the National Academy of Sciences of USA
UR  - http://dx.doi.org/10.1073/pnas.2006965117
UR  - https://www.ncbi.nlm.nih.gov/pubmed/32651268
UR  - https://www.pnas.org/content/early/2020/07/09/2006965117
UR  - http://hdl.handle.net/10044/1/80632
VL  - 117
ER  - 

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