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Cochlear nucleus spatial transcriptomes of normal and hearing loss mice reveal a critical role of Spp1 in bushy cells

Huihui Liu^1,2,3,† , Shangfeng Liao^4,5,† , Xiaowei Li^4,† , Li Song^6,7,† , Mu-Ming Poo⁸ , Jing Zhao^4,5 , Weijun Zhou^1,2,3 , Ruijie Cai^1,2,3 , Meijian Wang^1,2,3 , Xiaotong Ma^1,2,3 , Shaohui Lin⁹ , Xingle Zhao^1,2,3 , Ningyuan Zhu^4,5 , Yuanwei Zhang^4,5 , Junpu Mei^4,5 , Lei Song^1,2,3 , Lijian Zhao^4,5 , Sidi Liu^1,2,3 , Ying Chen^1,2,3 , Hao Wu^1,2,3,*

¹Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
²Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
³Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China
⁴BGI Research, Shenzhen, Guangdong, China
⁵BGI Research, Sanya, Hainan, China
⁶Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
⁷Department of Pathology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
⁸Center for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, Chinese Academy of Sciences, Shanghai, China
⁹Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
^†These authors contributed equally: Huihui Liu, Shangfeng Liao, Xiaowei Li, Li Song
* Correspondence: Hao Wu(wuhao@shsmu.edu.cn)

The molecular and cellular mechanisms underlying the function of the cochlear nucleus (CN) remain to be fully elucidated. Using single-nucleus RNA sequencing and single-cell spatial transcriptome analyses, we generated a comprehensive cell type atlas of the mouse CN, identified molecularly defined CN subregions, and quantified changes in gene expression and the spatial organization of CN cells in normal mice during postnatal development and in mutant mice with congenital hearing loss. We further identified a subtype of bushy cells expressing the osteopontin-encoding gene Spp1 as the primary CN cell type that exhibited hearing loss-induced alteration of gene expression. Among the highly affected genes in bushy cells, deletion of the auditory input-regulated gene Spp1 affected CN processing of auditory signals in mice. These results provide the most comprehensive cellular and molecular database to date for understanding auditory processing within the CN and identifying potential therapeutic targets for hearing restoration at the CN level.

https://doi.org/10.1038/s41422-026-01246-4

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