Novel crosstalk between Vps26a and Nox4 signaling during neurogenesis

Seon A. Choi, Young Hyun Kim, Young Ho Park, Hae Jun Yang, Pil Soo Jeong, Jae Jin Cha, Seung Bin Yoon, Ji Su Kim, Bong Seok Song, Jong Hee Lee, Bo Woong Sim, Jae Won Huh, In Sung Song, Sang Rae Lee, Min Kyu Kim, Jin Man Kim, Yun Soo Bae, Kazuhiko Imakawa, Sun Uk Kim, Kyu Tae Chang

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Despite numerous studies on the molecular switches governing the conversion of stemness to differentiation in embryonic stem cells (ESCs), little is known about the involvement of the retromer complex. Under neural differentiation conditions, Vps26a deficiency (Vps26a-/-) or knockdown suppressed the loss of stemness and subsequent neurogenesis from ESCs or embryonic carcinoma cells, respectively, as evidenced by the long-lasting expression of stemness markers and the slow appearance of neuronal differentiation markers. Interestingly, relatively low reactive oxygen species (ROS) levels were generated during differentiation of Vps26a-/- ESCs, and treatment with an antioxidant or inhibitor of NADPH oxidase (Nox), a family of ROS-generating enzymes, led to restoration of stemness in wild-type cells to the level of Vps26a-/- cells during neurogenesis. Importantly, a novel interaction between Vps26a and Nox4 linked to the activation of ERK1/2 depended highly on ROS levels during neurogenesis, which were strongly suppressed in differentiating Vps26a-/- ESCs. Moreover, inhibition of phosphorylated ERK1/2 (pERK1/2) resulted in decreased ROS and Nox4 levels, indicating the mutual dependency between pERK1/2 and Nox4-derived ROS during neurogenesis. These results suggest that Vps26a regulates stemness by actively cooperating with the Nox4/ROS/ERK1/2 cascade during neurogenesis. Our findings have important implications for understanding the regulation of stemness via crosstalk between the retromer molecule and redox signaling, and may contribute to the development of ESC-based therapeutic strategies for the mass production of target cells.

Original languageEnglish
Pages (from-to)1582-1599
Number of pages18
JournalCell Death and Differentiation
Volume26
Issue number9
DOIs
StatePublished - 1 Sep 2019

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