The subcommissural organ regulates brain development via secreted peptides

Tingting Zhang; Daosheng Ai; Pingli Wei; Ying Xu; Zhanying Bi; Fengfei Ma; Fengzhi Li; Xing-Jun Chen; Zhaohuan Zhang; Xiaoxiao Zou; Zongpei Guo; Yue Zhao; Jun-Liszt Li; Meng Ye; Ziyan Feng; Xinshuang Zhang; Lijun Zheng; Jie Yu; Chunli Li; Tianqi Tu; Hongkui Zeng; Jianfeng Lei; Hongqi Zhang; Tao Hong; Li Zhang; Benyan Luo; Zhen Li; Chao Xing; Chenxi Jia; Lingjun Li; Wenzhi Sun; Woo-Ping Ge

doi:10.1038/s41593-024-01639-x

The subcommissural organ regulates brain development via secreted peptides

Nat Neurosci. 2024 May 13. doi: 10.1038/s41593-024-01639-x. Online ahead of print.

Authors

Tingting Zhang^{1

2}, Daosheng Ai^{1

2}, Pingli Wei³, Ying Xu^{4

5}, Zhanying Bi^{2

6}, Fengfei Ma³, Fengzhi Li^{2

7}, Xing-Jun Chen^{1

2}, Zhaohuan Zhang⁸, Xiaoxiao Zou^{2

9}, Zongpei Guo², Yue Zhao², Jun-Liszt Li^{1

2}, Meng Ye^{2

9

10}, Ziyan Feng², Xinshuang Zhang², Lijun Zheng^{2

10}, Jie Yu^{2

11}, Chunli Li¹², Tianqi Tu¹³, Hongkui Zeng¹⁴, Jianfeng Lei¹⁵, Hongqi Zhang¹³, Tao Hong¹³, Li Zhang², Benyan Luo¹¹, Zhen Li², Chao Xing¹⁶, Chenxi Jia⁵, Lingjun Li¹⁷, Wenzhi Sun^{18

19}, Woo-Ping Ge^{20

21

22}

Affiliations

¹ Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
² Chinese Institute for Brain Research, Beijing, China.
³ Department of Chemistry and School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA.
⁴ School of Basic Medical Sciences, Anhui Medical University, Hefei, China.
⁵ State Key Laboratory of Proteomics, National Center for Protein Sciences-Beijing, Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, China.
⁶ College of Life Sciences, Nankai University, Tianjin, China.
⁷ State Key Laboratory of Cognitive Neuroscience and Learning and IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, China.
⁸ Department of Laboratory Medicine, Changzheng Hospital, Naval Medical University, Shanghai, China.
⁹ Changping Laboratory, Beijing, China.
¹⁰ School of Basic Medical Sciences, Capital Medical University, Beijing, China.
¹¹ Department of Neurology, First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China.
¹² National Institute of Biological Sciences, Beijing, China.
¹³ Department of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, Beijing, China.
¹⁴ Allen Institute for Brain Science, Seattle, WA, USA.
¹⁵ Medical Imaging laboratory of Core Facility Center, Capital Medical University, Beijing, China.
¹⁶ Eugene McDermott Center for Human Growth and Development, Department of Bioinformatics, School of Public Health, UT Southwestern Medical Center, Dallas, TX, USA.
¹⁷ Department of Chemistry and School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA. lingjun.li@wisc.edu.
¹⁸ Chinese Institute for Brain Research, Beijing, China. sunwenzhi@cibr.ac.cn.
¹⁹ School of Basic Medical Sciences, Capital Medical University, Beijing, China. sunwenzhi@cibr.ac.cn.
²⁰ Chinese Institute for Brain Research, Beijing, China. woopingge@cibr.ac.cn.
²¹ Changping Laboratory, Beijing, China. woopingge@cibr.ac.cn.
²² Department of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, Beijing, China. woopingge@cibr.ac.cn.

PMID: 38741020
DOI: 10.1038/s41593-024-01639-x

Abstract

The subcommissural organ (SCO) is a gland located at the entrance of the aqueduct of Sylvius in the brain. It exists in species as distantly related as amphioxus and humans, but its function is largely unknown. Here, to explore its function, we compared transcriptomes of SCO and non-SCO brain regions and found three genes, Sspo, Car3 and Spdef, that are highly expressed in the SCO. Mouse strains expressing Cre recombinase from endogenous promoter/enhancer elements of these genes were used to genetically ablate SCO cells during embryonic development, resulting in severe hydrocephalus and defects in neuronal migration and development of neuronal axons and dendrites. Unbiased peptidomic analysis revealed enrichment of three SCO-derived peptides, namely, thymosin beta 4, thymosin beta 10 and NP24, and their reintroduction into SCO-ablated brain ventricles substantially rescued developmental defects. Together, these data identify a critical role for the SCO in brain development.