dysfusion negatively regulates JAK/STAT signaling to constraint the invasive cell population
Authors: Jhen-Wei WU 1; Chueh-Wen Wang 1; Ruo-Yu Chen 1; Liang-Yi Hung 1; Yu-Chen Tsai 3; Yu-Ting Chan 1; Yu-Chiuan Chang 2; Anna C-C Jang 1
Affiliations: 1) Department of Biotechnology and Bioindustry Sciences National Cheng Kung University, 1 University Rd, Tainan City 70101, Taiwan; 2) Institute of Biomedical Sciences, National Sun Yat-sen University, 70 Lien-Hai Rd, Kaohsiung 804, Taiwan; 3) Department of Life Science and Life Science Center, Tunghai University, No.1727, Sec.4, Taiwan Boulevard, Taichung City 407224, Taiwan
Keywords: p. cell migration; e. JAK/STAT
Cell migration is a critical process for embryonic development and cancer metastasis. How the epithelial cells are selected and adapt migratory cell fate remains unclear. To decipher the underlying mechanism, we apply border cells (BCs), a small group of cells disseminating from the epithelium and migrating through germ cells Drosophila oogenesis, as a model to study collective cell movement. In a forward genetic screen, we found that overexpression of dysfusion (dysf) which severely impeded BC migration. Functional analysis further shows that depletion of dysf in BCs completely blocked cell mobility but that in polar cells, a specialized pair of cells secreting Upd to transactivate JAK/STAT signaling in the neighboring cells to form a cluster, leads to 64% of BC migration delay. These results indicate the requirement of Dysf in both border and polar cells during migration. Interestingly, overexpression of UAS-dysf in BCs hampered the recruitment, only 3.2 BC observed in the cohort, in comparison to 6 BC in the wild type. To teste whether the reduction of BC number result from JAK/STAT signaling hypoactivation, we examined STAT activity by STAT-GFP reporter under dysf overexpression. In wild type BCs, the intensity of STAT-GFP gradually increased during migration, but ectopically upregulated in the dysf mutant cells, and extra border cells were also observed simultaneously. Consistently, the ectopic BC phenotype caused by JAK or Upd overexpression can be suppressed by overexpression of UAS-dysf. Interestingly, Dysf protein is resided at the nuclear membrane of all germline and follicle cells but specifically reduced in BCs upon migration. When BCs reach the destiny, oocyte, their Dysf becomes undetectable. Moreover, we observed that nuclear/cytosol (N/C) ratio of STAT was greatly reduced up overexpression of dysf in the salivary gland. To elucidate how Dysf regulatess STAT nuclear transport, we carried out a biochemical screen to seek for interacting proteins with endogenous knock-in tagged Dysf. We found that Pendulin, a member of the Importin-alpha protein family, interact with Dysf. Therefore, we propose that dysf may determine the size of border cell clusters by regulating JAK/STAT signaling.