TY - JOUR TI - AGS3 antagonizes LGN to balance oriented cell divisions and cell fate choices in mammalian epidermis AU - Descovich, Carlos P AU - Lough, Kendall J AU - Jena, Akankshya AU - Wu, Jessica J AU - Yom, Jina AU - Spitzer, Danielle C AU - Uppalapati, Manuela AU - Kedziora, Katarzyna M AU - Williams, Scott E A2 - Yamashita, Yukiko M A2 - Akhmanova, Anna A2 - Yamashita, Yukiko M A2 - Bergstralh, Dan A2 - Prehoda, Kenneth E VL - 12 PY - 2023 DA - 2023/04/05 SP - e80403 C1 - eLife 2023;12:e80403 DO - 10.7554/eLife.80403 UR - https://doi.org/10.7554/eLife.80403 AB - 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 on how spindle orientation influences epidermal stratification. KW - oriented cell divisions KW - spindle orientation KW - epithelial cells KW - epidermis JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -