STRIPAK Members Orchestrate Hippo and Insulin Receptor Signaling to Promote Neural Stem Cell Reactivation

Highlights

• Transcriptional profiling of reactivating versus quiescent NSCs identifies STRIPAK members

• PP2A/Mts phosphatase inhibits Akt activation, maintaining NSC quiescence

• Mob4 and Cka target Mts to Hippo to inhibit its activity and promote NSC reactivation

• Mob4/Cka/Mts coordinate Hippo and InR/PI3K/Akt signaling in NSCs

Summary

Adult stem cells reactivate from quiescence to maintain tissue homeostasis and in response to injury. How the underlying regulatory signals are integrated is largely unknown. Drosophila neural stem cells (NSCs) also leave quiescence to generate adult neurons and glia, a process that is dependent on Hippo signaling inhibition and activation of the insulin-like receptor (InR)/PI3K/Akt cascade. We performed a transcriptome analysis of individual quiescent and reactivating NSCs harvested directly from Drosophila brains and identified the conserved STRIPAK complex members mob4, cka, and PP2A (microtubule star, mts). We show that PP2A/Mts phosphatase, with its regulatory subunit Widerborst, maintains NSC quiescence, preventing premature activation of InR/PI3K/Akt signaling. Conversely, an increase in Mob4 and Cka levels promotes NSC reactivation. Mob4 and Cka are essential to recruit PP2A/Mts into a complex with Hippo kinase, resulting in Hippo pathway inhibition. We propose that Mob4/Cka/Mts functions as an intrinsic molecular switch coordinating Hippo and InR/PI3K/Akt pathways and enabling NSC reactivation.