Involvement of LIN28A in Wnt-dependent regulation of hippocampal neurogenesis in the aging brain

Zhechun Hu; Jiao Ma; Huimin Yue; Yujian Luo; Xiaofang Li; Chao Wang; Liang Wang; Binggui Sun; Zhong Chen; Lang Wang; Yan Gu

doi:10.1016/j.stemcr.2022.05.016

Involvement of LIN28A in Wnt-dependent regulation of hippocampal neurogenesis in the aging brain

Stem Cell Reports. 2022 Jul 12;17(7):1666-1682. doi: 10.1016/j.stemcr.2022.05.016. Epub 2022 Jun 23.

Authors

Zhechun Hu¹, Jiao Ma², Huimin Yue¹, Yujian Luo², Xiaofang Li², Chao Wang¹, Liang Wang³, Binggui Sun⁴, Zhong Chen⁵, Lang Wang⁶, Yan Gu⁷

Affiliations

¹ Center of Stem Cell and Regenerative Medicine and Department of Neurology of the Second Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China.
² Department of Neurology of the First Affiliated Hospital, Interdisciplinary Institute of Neuroscience and Technology, Zhejiang University School of Medicine, Hangzhou 310029, China.
³ Institute of Neuroscience and Department of Neurology of the Second Affiliated Hospital, Mental Health Center, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China.
⁴ NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou 310058, China; MOE Frontier Science Center for Brain Science & Brain-Machine Integration, Zhejiang University, Hangzhou 310058, China.
⁵ Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
⁶ Department of Neurology of the First Affiliated Hospital, Interdisciplinary Institute of Neuroscience and Technology, Zhejiang University School of Medicine, Hangzhou 310029, China. Electronic address: wanglang@zju.edu.cn.
⁷ Center of Stem Cell and Regenerative Medicine and Department of Neurology of the Second Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China; MOE Frontier Science Center for Brain Science & Brain-Machine Integration, Zhejiang University, Hangzhou 310058, China. Electronic address: guyan2015@zju.edu.cn.

Abstract

Hippocampal neurogenesis declines with aging. Wnt ligands and antagonists within the hippocampal neurogenic niche regulate the proliferation of neural progenitor cells and the development of new neurons, and the changes of their levels in the niche mediate aging-associated decline of neurogenesis. We found that RNA-binding protein LIN28A remained existent in neural progenitor cells and granule neurons in the adult hippocampus and that it decreased with aging. Lin28a knockout inhibited the responsiveness of neural progenitor cells to niche Wnt agonists and reduced neurogenesis, thus impairing pattern separation. Overexpression of Lin28a increased the proliferation of neural progenitor cells, promoted the functional integration of newborn neurons, restored neurogenesis in Wnt-deficient dentate gyrus, and rescued the impaired pattern separation in aging mice. Our data suggest that LIN28A regulates adult hippocampal neurogenesis as an intracellular mechanism by responding to niche Wnt signals, and its decrease is involved in aging-associated decline of hippocampal neurogenesis and related cognitive functions.

Keywords: LIN28A; Wnt; adult neurogenesis; aging; hippocampus.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aging / physiology
Animals
Brain
Dentate Gyrus / metabolism
Hippocampus / metabolism
Mice
Neural Stem Cells* / metabolism
Neurogenesis* / physiology