Fucosyltransferase 8 regulates adult neurogenesis and cognition of mice by modulating the Itga6-PI3K/Akt signaling pathway

Hongfeng Guo; Qihang Sun; Xiaoli Huang; Xiaohao Wang; Feng Zhang; Wenzheng Qu; Jinling Liu; Xuejun Cheng; Qiang Zhu; Wen Yi; Qiang Shu; Xuekun Li

doi:10.1007/s11427-023-2510-0

Fucosyltransferase 8 regulates adult neurogenesis and cognition of mice by modulating the Itga6-PI3K/Akt signaling pathway

Sci China Life Sci. 2024 Mar 22. doi: 10.1007/s11427-023-2510-0. Online ahead of print.

Authors

Hongfeng Guo^#^{1

2}, Qihang Sun^#^{1

2}, Xiaoli Huang^#¹, Xiaohao Wang^#¹, Feng Zhang¹, Wenzheng Qu¹, Jinling Liu¹, Xuejun Cheng¹, Qiang Zhu³, Wen Yi³, Qiang Shu⁴, Xuekun Li^{5

6

7

8}

Affiliations

¹ The Children's Hospital, National Clinical Research Center for Child Health, School of Medicine, Zhejiang University, Hangzhou, 310052, China.
² The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, 310029, China.
³ College of Life Sciences, Zhejiang University, Hangzhou, 310058, China.
⁴ The Children's Hospital, National Clinical Research Center for Child Health, School of Medicine, Zhejiang University, Hangzhou, 310052, China. shuqiang@zju.edu.cn.
⁵ The Children's Hospital, National Clinical Research Center for Child Health, School of Medicine, Zhejiang University, Hangzhou, 310052, China. xuekun_li@zju.edu.cn.
⁶ The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, 310029, China. xuekun_li@zju.edu.cn.
⁷ Binjiang Institute of Zhejiang University, Hangzhou, 310053, China. xuekun_li@zju.edu.cn.
⁸ Zhejiang University Cancer Center, Zhejiang University, Hangzhou, 310029, China. xuekun_li@zju.edu.cn.

^# Contributed equally.

PMID: 38523237
DOI: 10.1007/s11427-023-2510-0

Abstract

Fucosyltransferase 8 (Fut8) and core fucosylation play critical roles in regulating various biological processes, including immune response, signal transduction, proteasomal degradation, and energy metabolism. However, the function and underlying mechanism of Fut8 and core fucosylation in regulating adult neurogenesis remains unknown. We have shown that Fut8 and core fucosylation display dynamic features during the differentiation of adult neural stem/progenitor cells (aNSPCs) and postnatal brain development. Fut8 depletion reduces the proliferation of aNSPCs and inhibits neuronal differentiation of aNSPCs in vitro and in vivo, respectively. Additionally, Fut8 deficiency impairs learning and memory in mice. Mechanistically, Fut8 directly interacts with integrin α6 (Itga6), an upstream regulator of the PI3k-Akt signaling pathway, and catalyzes core fucosylation of Itga6. Deletion of Fut8 enhances the ubiquitination of Itga6 by promoting the binding of ubiquitin ligase Trim21 to Itga6. Low levels of Itga6 inhibit the activity of the PI3K/Akt signaling pathway. Moreover, the Akt agonist SC79 can rescue neurogenic and behavioral deficits caused by Fut8 deficiency. In summary, our study uncovers an essential function of Fut8 and core fucosylation in regulating adult neurogenesis and sheds light on the underlying mechanisms.

Keywords: Fut8; Itga6; PI3K/Akt; adult neural stem/progenitor cells; neurogenesis.