The phospholipid scramblase PLSCR5 is regulated by POU4F3 and required for hair cell stereocilia homeostasis and auditory functions

Sihao Gong; Qing Liu; Haibo Du; Linqing Zhang; Chengwen Zhu; Zhigang Xu; Xia Gao; Guang-Jie Zhu; Guoqiang Wan

doi:10.1016/j.jgg.2025.03.003

The phospholipid scramblase PLSCR5 is regulated by POU4F3 and required for hair cell stereocilia homeostasis and auditory functions

J Genet Genomics. 2025 Mar 9:S1673-8527(25)00072-4. doi: 10.1016/j.jgg.2025.03.003. Online ahead of print.

Authors

Sihao Gong¹, Qing Liu², Haibo Du³, Linqing Zhang¹, Chengwen Zhu⁴, Zhigang Xu³, Xia Gao⁵, Guang-Jie Zhu⁶, Guoqiang Wan⁷

Affiliations

¹ MOE Key Laboratory of Model Animal for Disease Study, Department of Otolaryngology Head and Neck Surgery, Jiangsu Provincial Key Medical Discipline (Laboratory), The Affiliated Drum Tower Hospital of Medical School and the Model Animal Research Center of Medical School, Nanjing University, Nanjing, Jiangsu 210008, China; State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Key Laboratory of Molecular Medicine, National Resource Center for Mutant Mice of China, Nanjing University, Nanjing, Jiangsu 210008, China.
² MOE Key Laboratory of Model Animal for Disease Study, Department of Otolaryngology Head and Neck Surgery, Jiangsu Provincial Key Medical Discipline (Laboratory), The Affiliated Drum Tower Hospital of Medical School and the Model Animal Research Center of Medical School, Nanjing University, Nanjing, Jiangsu 210008, China; State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Key Laboratory of Molecular Medicine, National Resource Center for Mutant Mice of China, Nanjing University, Nanjing, Jiangsu 210008, China; Research Institute of Otolaryngology, No. 321 Zhongshan Road, Nanjing, Jiangsu 210008, China.
³ Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology and Key Laboratory for Experimental Teratology of the Ministry of Education, School of Life Sciences, Shandong University, Qingdao, Shandong 266237, China.
⁴ MOE Key Laboratory of Model Animal for Disease Study, Department of Otolaryngology Head and Neck Surgery, Jiangsu Provincial Key Medical Discipline (Laboratory), The Affiliated Drum Tower Hospital of Medical School and the Model Animal Research Center of Medical School, Nanjing University, Nanjing, Jiangsu 210008, China; Research Institute of Otolaryngology, No. 321 Zhongshan Road, Nanjing, Jiangsu 210008, China.
⁵ MOE Key Laboratory of Model Animal for Disease Study, Department of Otolaryngology Head and Neck Surgery, Jiangsu Provincial Key Medical Discipline (Laboratory), The Affiliated Drum Tower Hospital of Medical School and the Model Animal Research Center of Medical School, Nanjing University, Nanjing, Jiangsu 210008, China; Research Institute of Otolaryngology, No. 321 Zhongshan Road, Nanjing, Jiangsu 210008, China. Electronic address: gaoxia@nju.edu.cn.
⁶ MOE Key Laboratory of Model Animal for Disease Study, Department of Otolaryngology Head and Neck Surgery, Jiangsu Provincial Key Medical Discipline (Laboratory), The Affiliated Drum Tower Hospital of Medical School and the Model Animal Research Center of Medical School, Nanjing University, Nanjing, Jiangsu 210008, China; Research Institute of Otolaryngology, No. 321 Zhongshan Road, Nanjing, Jiangsu 210008, China. Electronic address: zhuzhugj@163.com.
⁷ MOE Key Laboratory of Model Animal for Disease Study, Department of Otolaryngology Head and Neck Surgery, Jiangsu Provincial Key Medical Discipline (Laboratory), The Affiliated Drum Tower Hospital of Medical School and the Model Animal Research Center of Medical School, Nanjing University, Nanjing, Jiangsu 210008, China; State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Key Laboratory of Molecular Medicine, National Resource Center for Mutant Mice of China, Nanjing University, Nanjing, Jiangsu 210008, China; Research Institute of Otolaryngology, No. 321 Zhongshan Road, Nanjing, Jiangsu 210008, China. Electronic address: guoqiangwan@nju.edu.cn.

PMID: 40068798
DOI: 10.1016/j.jgg.2025.03.003

Abstract

Hearing relies on the structural and functional integrity of cochlear hair cells, particularly their apical F-actin-filled stereocilia. Phospholipid scramblases are important for maintaining membrane asymmetry, but their roles in the stereocilia and auditory functions are not fully understood. Here, we identify Plscr5 as a downstream target of the transcription factor POU4F3 essential for hair cell function, whose mutation causes human DFNA15 deafness. Plscr5 knockout mice exhibit progressive hearing loss due to stereocilia degeneration and hair cell loss. Functional analyses reveal that PLSCR5 contributes to phosphatidylserine externalization in hair cell apical membranes, particularly in inner hair cells, and is important for outer hair cell and stereocilia maintenance. Our findings highlight PLSCR5 as an important downstream effector of POU4F3 and regulator of PS externalization and membrane dynamics required for auditory functions.

Keywords: Hair cell; Hearing loss; PLSCR5; POU4F3; Phosphatidylserine; Phospholipid scramblase; Stereocilia.