Our brains are notoriously bad at regenerating cells that have been lost through injury or disease. While therapies using neural stem cells (NSCs) hold the promise of replacing lost cells, scientists need to better understand how NSCs behave in the brain in order to develop effective treatments.
Now research published in Cell Reports helps to shed new light on the mechanisms used by NSCs to 'wake up' - going from their usual dormant state to one of action.
NSCs produce neurons (nerve cells) and surrounding glial cells in the brain. By understanding how NSCs work, it could pave the way for therapies to speed up the neurons' and glial cells' regeneration.
The new study, conducted using Drosophila fruit flies, shows that molecules that form a complex called STRIPAK are essential to promote reactivation in NSCs. STRIPAK (Striatin-interacting phosphatase and kinase) is found in organisms from fungi to humans, and the team uncovered it when comparing the genetic messages of dormant and reactivated NSCs in live fly brains.
The researchers then discovered that STRIPAK components act as a switch to turn off dormancy (or quiescence) and turn on reactivation. The authors 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).
They 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. Authors propose that Mob4/Cka/Mts functions as an intrinsic molecular switch coordinating Hippo and InR/PI3K/Akt pathways and enabling NSC reactivation.
Lead author acknowledges there is still a long way to go until such findings can be translated into human treatments. But she explains the significance of the new work:
"So little is currently known about how neural stem cells coordinate cues to become active and direct the production of more brain cells," the lead said. "These stem cells last throughout life mainly in a dormant state, so learning how they work is critical to our understanding of cell regeneration.
"This study reveals that STRIPAK molecules are essential to enable reactivation in NSCs, and we are very pleased with the outcomes. But we are only at the beginning. We are working to expand our findings and bring us closer to the day when human neural stem cells can be controlled and efficiently used to facilitate brain damage repair, or even prevent brain cancer growth that is fuelled by stem-like cells."
Activating sleeping brain stem cells
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