JNK-mediated spindle reorientation in stem cells promotes dysplasia in the aging intestine

Abstract Homeostasis in high-turnover tissues depends on precise yet plastic regulation of stem cell daughter fates. In Drosophila , intestinal stem cells (ISCs) respond to unknown signals to switch from asymmetric to symmetric divisions during feeding-induced growth. Here, we show that this switch is controlled by dynamic reorientation of mitotic spindles by a Jun-N-terminal Kinase (JNK) / Wdr62 / Kif1a interaction. JNK promotes Wdr62 localization at the spindle and represses transcription of the kinesin Kif1a. This activity of JNK results in over-abundance of symmetric divisions in stress conditions, and contributes to the loss of tissue homeostasis in the aging animal. Restoring normal ISC spindle orientation by perturbing the JNK/Wdr62/Kif1a axis is sufficient to improve intestinal physiology and extend lifespan. Our findings reveal a critical role for the dynamic control of SC spindle orientation in epithelial maintenance.