Ttyh1 regulates embryonic neural stem cell properties by enhancing the Notch signaling pathway

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.

Neural G0: a quiescent-like state found in neuroepithelial-derived cells and glioma

“…Moreover, multiple Neural G0 genes are significantly enriched in NSCs and glioma Neural G0 cells which are known to help maintain "stemness". For example, HEY1 and TTYH1 (e.g., Fig S3), are both are key players in Notch signaling pathway in NSCs and help maintain the NSC identity in vivo (Kim et al 2018;Than-Trong et al 2018). PTN and its target PTPRZ1 also may help promote stemness, signaling, and proliferation of neural progenitors and glioma tumor cells (Fujikawa et al 2016;Zhang et al 2016;Fujikawa et al 2017).…”

ETMR: a tumor entity in its infancy

“…It is not clear whether TTYH1 plays a role in ETMRs, since apart from encoding a chloride anion channel and being expressed in brain, eye, testis and ovary, the function of the TTYH1 protein is currently not well understood [49,125]. Possibly TTYH1 plays a role in the differentiation of neural stem cells during brain development [70,143], where TTYH1 is mainly expressed in neural stem cells, neurons and astrocytes [141]. The cell of origin of ETMRs is currently not known, but there are indications that ETMRs resemble a broad spectrum of developmental stages ranging from neural stem cells and early radial glia to a more differentiated lineage such as astrocytes and neurons based on histology [32,43,77], expressed markers [76,98,124], and single cell RNA sequencing [64].…”

GemC1 is a critical switch for neural stem cell generation in the postnatal brain

“…A characteristic example is that of the Blbp promoter (also known as Fabp7 ), which was found to be more “open,” consistent with our in vivo data indicating its high expression in GemC1 KO/KO cells. Other examples of NSC‐like genes that seem more “active” upon GemC1 deletion include GFAP and Gja1 (Dulken et al, ) and Ttyh1, which is characterized as a positive regulator of Notch signaling pathway (Kim et al, ). Moreover, several Notch elements (such as Notch1, Jag1, Dll1, and Rbpj) normally expressed in adult NSCs, acquire more “accessible” chromatin organization upon GemC1 deletion.…”

“…GemC1 KO/KO cells. Other examples of NSC-like genes that seem more "active" upon GemC1 deletion include GFAP and Gja1 (Dulken et al, 2017) and Ttyh1, which is characterized as a positive regulator of Notch signaling pathway (Kim et al, 2018). Moreover, several Notch elements (such as Notch1, Jag1, Dll1, and Rbpj) normally expressed in adult NSCs, acquire more "accessible" chromatin organization upon GemC1 deletion.…”