AI Article Synopsis
- Ttyh1 is essential for maintaining neural stem cell properties, as shown by its impact on neurosphere formation and cell localization.
- Enhanced activity of γ-secretase leads to increased Notch intracellular domain (NICD) production, which enhances the stemness of neural stem cells through Ttyh1's unique function.
- Ttyh1 interacts with the Rer1 protein in the endoplasmic reticulum to destabilize it, thereby boosting γ-secretase activity and positively regulating the Notch signaling pathway, crucial for mammalian brain development.
Article Abstract
Despite growing evidence linking tweety-homologue 1 (Ttyh1) to normal mammalian brain development and cell proliferation, its exact role has not yet been determined. Here, we show that Ttyh1 is required for the maintenance of neural stem cell (NSC) properties as assessed by neurosphere formation and analyses of cell localization after electroporation. We find that enhanced Ttyh1-dependent stemness of NSCs is caused by enhanced γ-secretase activity resulting in increased levels of Notch intracellular domain (NICD) production and activation of Notch targets. This is a unique function of Ttyh1 among all other Ttyh family members. Molecular analyses revealed that Ttyh1 binds to the regulator of γ-secretase activity Rer1 in the endoplasmic reticulum and thereby destabilizes Rer1 protein levels. This is the key step for Ttyh1-dependent enhancement of γ-secretase activity, as Rer1 overexpression completely abolishes the effects of Ttyh1 on NSC maintenance. Taken together, these findings indicate that Ttyh1 plays an important role during mammalian brain development by positively regulating the Notch signaling pathway through the downregulation of Rer1.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6216262 | PMC |
| http://dx.doi.org/10.15252/embr.201745472 | DOI Listing |
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