The Drosophila Ortholog of Mammalian Transcription Factor Sox9 Regulates Intestinal Homeostasis and Regeneration at an Appropriate Level

• Published in: Cell reports (Cambridge) 2020-05, Vol.31 (8), p.107683-107683, Article 107683
• Main Authors: Jin, Zhen, Chen, Jun, Huang, Huanwei, Wang, Jiawen, Lv, Jiaying, Yu, Menghan, Guo, Xingting, Zhang, Yongchao, Cai, Tao, Xi, Rongwen
• Format: Article
• Language: English
• Subjects: cell division; cell fate determination; dosage effect; dosage-dependent; dSox9; intestinal epithelium; recovery; tissue-damage; tumorigenesis
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.107683

Balanced stem cell self-renewal and differentiation is essential for maintaining tissue homeostasis, but the underlying mechanisms are poorly understood. Here, we identified the transcription factor SRY-related HMG-box (Sox) 100B, which is orthologous to mammalian Sox8/9/10, as a common target and central mediator of the EGFR/Ras and JAK/STAT signaling pathways that coordinates intestinal stem cell (ISC) proliferation and differentiation during both normal epithelial homeostasis and stress-induced intestinal repair in Drosophila. The two stress-responsive pathways directly regulate Sox100B transcription via two separate enhancers. Interestingly, an appropriate level of Sox100B is critical for its function, as its depletion inhibits ISC proliferation via cell cycle arrest, while its overexpression also inhibits ISC proliferation by directly suppressing EGFR expression and additionally promotes ISC differentiation by activating a differentiation-promoting regulatory circuitry composed of Sox100B, Sox21a, and Pdm1. Thus, our study reveals a Sox family transcription factor that functions as a stress-responsive signaling nexus that ultimately controls tissue homeostasis and regeneration. [Display omitted] •dSox9/Sox100B promotes ISC proliferation only at an appropriate level•Sox100B is directly induced by both JAK/STAT and EGFR/Ras signaling pathways•Sox100B overexpression inhibits MAPK signaling by suppressing EGFR expression•Sox100B promotes cell differentiation via a Sox100B-Sox21a-Pdm1 regulatory circuitry Jin et al. report that the Drosophila Sox9 ortholog functions downstream of EGFR and JAK/STAT signaling pathways, and that its expression modulation is critical for coordinated ISC proliferation and differentiation during intestinal homeostasis and regeneration.