WWC1/2 regulate spinogenesis and cognition in mice by stabilizing AMOT

Runyi Cao; Rui Zhu; Zhao Sha; Sixian Qi; Zhenxing Zhong; Fengyun Zheng; Yubin Lei; Yanfeng Tan; Yuwen Zhu; Yu Wang; Yi Wang; Fa-Xing Yu

doi:10.1038/s41419-023-06020-7

WWC1/2 regulate spinogenesis and cognition in mice by stabilizing AMOT

Cell Death Dis. 2023 Aug 1;14(8):491. doi: 10.1038/s41419-023-06020-7.

Authors

Runyi Cao^#¹, Rui Zhu^#¹, Zhao Sha¹, Sixian Qi¹, Zhenxing Zhong¹, Fengyun Zheng¹, Yubin Lei¹, Yanfeng Tan¹, Yuwen Zhu¹, Yu Wang², Yi Wang³, Fa-Xing Yu⁴

Affiliations

¹ Institute of Pediatrics, Children's Hospital of Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, The International Co-laboratory of Medical Epigenetics and Metabolism, the State Key Laboratory of Genetic Engineering, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
² Institute of Pediatrics, Children's Hospital of Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, The International Co-laboratory of Medical Epigenetics and Metabolism, the State Key Laboratory of Genetic Engineering, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China. fd_wangyu@fudan.edu.cn.
³ Department of Neurology, Children's Hospital of Fudan University, National Children's Medical Center, No. 399 Wanyuan Road, Shanghai, 201102, China. yiwang@shmu.edu.cn.
⁴ Institute of Pediatrics, Children's Hospital of Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, The International Co-laboratory of Medical Epigenetics and Metabolism, the State Key Laboratory of Genetic Engineering, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China. fxyu@fudan.edu.cn.

^# Contributed equally.

Abstract

WWC1 regulates episodic learning and memory, and genetic nucleotide polymorphism of WWC1 is associated with neurodegenerative diseases such as Alzheimer's disease. However, the molecular mechanism through which WWC1 regulates neuronal function has not been fully elucidated. Here, we show that WWC1 and its paralogs (WWC2/3) bind directly to angiomotin (AMOT) family proteins (Motins), and recruit USP9X to deubiquitinate and stabilize Motins. Deletion of WWC genes in different cell types leads to reduced protein levels of Motins. In mice, neuron-specific deletion of Wwc1 and Wwc2 results in reduced expression of Motins and lower density of dendritic spines in the cortex and hippocampus, in association with impaired cognitive functions such as memory and learning. Interestingly, ectopic expression of AMOT partially rescues the neuronal phenotypes associated with Wwc1/2 deletion. Thus, WWC proteins modulate spinogenesis and cognition, at least in part, by regulating the protein stability of Motins.

Publication types

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

MeSH terms

Angiomotins*
Animals
Cognition
Hippocampus / physiology
Learning*
Mice
Microfilament Proteins
Neurons

Substances

Angiomotins
Microfilament Proteins