AGS3 antagonizes LGN to balance oriented cell divisions and cell fate choices in mammalian epidermis
Oriented cell divisions balance self-renewal and differentiation in stratified epithelia such as the skin epidermis. During peak epidermal stratification, the distribution of division angles among basal keratinocyte progenitors is bimodal, with planar and perpendicular divisions driving symmetric and asymmetric daughter cell fates, respectively. An apically-restricted, evolutionarily-conserved spindle orientation complex that includes the scaffolding protein LGN/Pins/Gpsm2 plays a central role in promoting perpendicular divisions and stratification, but why only a subset of cell polarize LGN is not known. Here, we demonstrate that the LGN paralog, AGS3/Gpsm1, is a novel negative regulator of LGN, and inhibits perpendicular divisions. Static and ex vivo live imaging reveal that AGS3 overexpression displaces LGN from the apical cortex and increases planar orientations, while AGS3 loss prolongs cortical LGN localization and leads to a perpendicular orientation bias. Genetic epistasis experiments in double mutants confirm that AGS3 operates through LGN. Finally, clonal lineage tracing shows that LGN and AGS3 promote asymmetric and symmetric fates, respectively, while also influencing differentiation through delamination. Collectively, these studies shed new light into how spindle orientation influences epidermal stratification.
All data generated or analyzed during this study are included in the manuscript and supporting file; Source Data files have been provided for data in all figures.
Article and author information
National Institutes of Health (R01 AR077591)
- Scott E Williams
United States - Israel Binational Science Foundation (2019230)
- Scott E Williams
Sidney Kimmel Foundation (SKF-15-065)
- Scott E Williams
Chan Zuckerberg Initiative (2020- 225716)
- Katarzyna M Kedziora
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols 19-155 and 22-121 at the University of North Carolina. All mice were housed in an AAALAC-accredited (#329; November, 2020), USDA registered (55-R-0004), NIH welfare-assured (D16-00256 (A3410-01) animal facility. All surgeries were performed under isoflurane anesthesia and meloxicam was alleviated post-operatively to minimize pain.
- Yukiko M Yamashita, Whitehead Institute/MIT, United States
- Received: May 19, 2022
- Preprint posted: May 20, 2022 (view preprint)
- Accepted: April 4, 2023
- Accepted Manuscript published: April 5, 2023 (version 1)
- Version of Record published: April 19, 2023 (version 2)
© 2023, Descovich et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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