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

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.