Control of Intestinal Cell Fate by Dynamic Mitotic Spindle Repositioning Influences Epithelial Homeostasis and Longevity

Abstract

Summary: Tissue homeostasis depends on precise yet plastic regulation of stem cell daughter fates. During growth, Drosophila intestinal stem cells (ISCs) adjust fates by switching from asymmetric to symmetric lineages to scale the size of the ISC population. Using a combination of long-term live imaging, lineage tracing, and genetic perturbations, we demonstrate that this switch is executed through the control of mitotic spindle orientation by Jun-N-terminal kinase (JNK) signaling. JNK interacts with the WD40-repeat protein Wdr62 at the spindle and transcriptionally represses the kinesin Kif1a to promote planar spindle orientation. In stress conditions, this function becomes deleterious, resulting in overabundance of symmetric fates and contributing 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. : Hu and Jasper demonstrate that spindle orientation regulates stem cell fate in Drosophila intestines. JNK activity promotes reorientation from oblique to planar spindles, increasing symmetric outcomes. This switch is required for growth but becomes chronic during stress and age. Restoring oblique spindles in old animals improves tissue physiology, extending lifespan. Keywords: JNK, spindle orientation, cell fate, intestinal stem cell, aging, Wdr62, Kif1a, regeneration, growth, Drosophila