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

Abstract

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.

MST4 kinase suppresses gastric tumorigenesis by limiting YAP activation via a non-canonical pathway

“…Membrane proteins including G-protein–coupled receptors have been proposed to relay extracellular signals to the intracellular Hippo kinase cascade (Yu et al, 2012). Besides, the striatin-interacting phosphatase and kinase (STRIPAK) complex was recently revealed to integrate upstream signals to trigger Hippo signaling in cells (Chen et al, 2019; Gil-Ranedo et al, 2019; Tang et al, 2019b). In the future, it would be intriguing to investigate whether these proteins are involved in the upstream regulation of the MST4–YAP signaling, especially in a context of tumorigenesis.…”

Msps Governs Acentrosomal Microtubule Assembly and Reactivation of Quiescent Neural Stem Cells

“…NSC reactivation also requires intrinsic mechanisms involving a transcription factor Prospero, spindle matrix proteins and striatin-interacting phosphatase and kinase (STRIPAK) family proteins (Gil-Ranedo et al, 2019;Lai and Doe, 2014a;Li et al, 2017).…”

Regenerative neurogenic response from glia requires insulin driven neuron-glia communication

“…In vertebrates and also in invertebrates, neural stem cells found after development in the adult CNS and upon injury, are generally distinct from developmental ones, and can originate from hemocytes, but most often, from glial cells (Falk and Gotz, 2017;Simoes and Rhiner, 2017;Tanaka and Ferretti, 2009). Our findings that Dilp6 and InR can induce dpn expression are reminiscent of their functions in the induction of neural stem cells from quiescent progenitors in development (Chell and Brand, 2010;Gil-Ranedo, et al, 2019;Sousa-Nunes, et al, 2011). However, the Dpn+ cells induced upon injury and after development, are distinct from the developmental neural stem cells normally induced by Dilp-6.…”

“…Amongst the novel hits, most prominent were genes encoding transmembrane protein phosphatases and insulin-related factors, including phosphatase LAR, Akt and phosphatase-dead ia-2 ( Supplementary Figure 2A-D). Ptp2A negatively regulates insulin receptor signaling, maintaining neural stem cell quiescence (Gil-Ranedo, et al, 2019). LAR is involved in neuronal axon guidance, and is responsible for de-phosphorylating, and thus inactivating, insulin receptor signaling (Mooney, et al, 1997;Wills, et al, 1999).…”