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Arp2/3 complex activity is necessary for mouse ESC differentiation, times formative pluripotency, and enables lineage specification

View ORCID ProfileFrancesca M. Aloisio, Diane L. Barber
doi: https://doi.org/10.1101/2021.11.02.465785
Francesca M. Aloisio
Department of Cell & Tissue Biology; University of California San Francisco; San Francisco, CA, 94143; USA
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  • ORCID record for Francesca M. Aloisio
Diane L. Barber
Department of Cell & Tissue Biology; University of California San Francisco; San Francisco, CA, 94143; USA
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  • For correspondence: diane.barber@ucsf.edu
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Summary

Mouse embryonic stem cells (mESCs), a model for differentiation into primed epiblast-like cells (EpiLCs), have revealed transcriptional and epigenetic control of early embryonic development. The control and significance of morphological changes, however, remain less defined. We show marked changes in morphology and actin architectures during differentiation that depend on Arp2/3 complex but not formin activity. Inhibiting Arp2/3 complex activity pharmacologically or genetically does not block exit from naive pluripotency but attenuates increases in EpiLC markers. We find that inhibiting Arp2/3 complex activity delays formative pluripotency and causes globally defective lineage specification as indicated by RNA-sequencing, with significant effects on TBX3-depedendent transcriptional programs. We also identify two previously unreported indicators of mESC differentiation; MRTF and FHL2, which have inverse Arp2/3 complex-dependent nuclear translocation. Our findings on Arp2/3 complex activity in differentiation and the established role of formins in EMT indicate that these two actin nucleators regulate distinct modes of epithelial plasticity.

Highlights

  • Arp2/3 complex activity is necessary for morphology changes during differentiation

  • Arp2/3 complex activity regulates transcriptional markers of differentiation

  • Inhibiting Arp2/3 complex activity delays entry into formative pluripotency

  • Arp2/3 complex activity-dependent shuttling of FHL2 and MRTF occurs in mESCs

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • eTOC Aloisio and Barber report a role for Arp2/3 complex activity in morphological and transcriptional changes with mESC differentiation. The authors reveal that inhibiting Arp2/3 complex activity delays entry into formative pluripotency, offering further mechanistic insight on this recently identified transition. Global examination of lineage specification using RNA-sequencing suggests a role for Arp2/3 complex activity in TBX3-dependent transcriptional programs during differentiation.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted November 04, 2021.
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Arp2/3 complex activity is necessary for mouse ESC differentiation, times formative pluripotency, and enables lineage specification
Francesca M. Aloisio, Diane L. Barber
bioRxiv 2021.11.02.465785; doi: https://doi.org/10.1101/2021.11.02.465785
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Arp2/3 complex activity is necessary for mouse ESC differentiation, times formative pluripotency, and enables lineage specification
Francesca M. Aloisio, Diane L. Barber
bioRxiv 2021.11.02.465785; doi: https://doi.org/10.1101/2021.11.02.465785

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