Upon the initiation of collective cell migration, cells at the free edge are specified as the leader cells; however, the mechanism underlying the leader cell specification remains elusive. Here, we show that lamellipodial extension after the release from mechanical confinement causes sustained ERK activation and underlies the leader cell specification. Live-imaging with FRET-based biosensors revealed that leader cells exhibit sustained ERK activation in an HGF-dependent manner. Meanwhile, follower cells exhibit oscillatory ERK activation waves in an EGF signaling-dependent manner. Lamellipodial extension at the free edge increases the cellular sensitivity to HGF. This HGF-dependent sustained ERK activation in turn promotes lamellipodial extension and traction force generation, thereby forming a positive feedback loop between cell extension and ERK activation, and specifying the cells at the free edge as the leader cells. Collectively, our findings reveal that integration of physical environment and biochemical cues underlies the leader cell specification during collective cell migration.
See details in Hino, N., Matsuda, K., Jikko, Y., Maryu, G., Sakai, K., Imamura, R., Tsukiji, S., Aoki, K., Terai, K., Hirashima, T., Trepat, X., Matsuda, M., 2022. A feedback loop between lamellipodial extension and HGF-ERK signaling specifies leader cells during collective cell migration. Developmental Cell 0. https://doi.org/10.1016/j.devcel.2022.09.003
See details in Hino et al., Developmental Cell (2022). Please see "readme.txt" files in each directory for the imaging conditions.
Naoya Hino, Kimiya Matsuda, Yuya Jikko, Gembu Maryu, Katsuya Sakai, Ryu Imamura, Shinya Tsukiji, Kazuhiro Aoki, Kenta Terai, Tsuyoshi Hirashima, Xavier Trepat, Michiyuki Matsuda (2022) A feedback loop between lamellipodial extension and HGF-ERK signaling specifies leader cells during collective cell migration., Developmental cell, Volume 57, Number 19, pp. 2290-2304.e7
Published in 2022 Oct 10 (Electronic publication in Sept. 28, 2022, midnight )
(Abstract) Upon the initiation of collective cell migration, the cells at the free edge are specified as leader cells; however, the mechanism underlying the leader cell specification remains elusive. Here, we show that lamellipodial extension after the release from mechanical confinement causes sustained extracellular signal-regulated kinase (ERK) activation and underlies the leader cell specification. Live-imaging of Madin-Darby canine kidney (MDCK) cells and mouse epidermis through the use of Forster resonance energy transfer (FRET)-based biosensors showed that leader cells exhibit sustained ERK activation in a hepatocyte growth factor (HGF)-dependent manner. Meanwhile, follower cells exhibit oscillatory ERK activation waves in an epidermal growth factor (EGF) signaling-dependent manner. Lamellipodial extension at the free edge increases the cellular sensitivity to HGF. The HGF-dependent ERK activation, in turn, promotes lamellipodial extension, thereby forming a positive feedback loop between cell extension and ERK activation and specifying the cells at the free edge as the leader cells. Our findings show that the integration of physical and biochemical cues underlies the leader cell specification during collective cell migration.(MeSH Terms)