A gain-of-function Retsat variant from high-altitude adaptation promotes myelination via a neuronal dihydroretinoic acid-RXR-γ pathway

Daopeng Li; Wenxiu Dai; Li Li; Zhihao Zhou; Zhenghao Li; Chenzhao He; Xiangying Li; Xiaoyun Lu; Qiuying Huang; Yanqin Zhu; Debao Wu; Jiaquan Lu; Yiting Yuan; Yanghanchen Zhao; Wenbiao Zhang; Zhiping Zeng; Qiuying Huang; Xuemin Wang; Peng Shi; Liang Zhang

doi:10.1016/j.neuron.2026.01.013

A gain-of-function Retsat variant from high-altitude adaptation promotes myelination via a neuronal dihydroretinoic acid-RXR-γ pathway

Neuron. 2026 Mar 13:S0896-6273(26)00013-9. doi: 10.1016/j.neuron.2026.01.013. Online ahead of print.

Authors

Daopeng Li¹, Wenxiu Dai², Li Li², Zhihao Zhou², Zhenghao Li³, Chenzhao He², Xiangying Li², Xiaoyun Lu², Qiuying Huang², Yanqin Zhu², Debao Wu², Jiaquan Lu², Yiting Yuan², Yanghanchen Zhao², Wenbiao Zhang⁴, Zhiping Zeng⁴, Qiuying Huang⁵, Xuemin Wang², Peng Shi⁶, Liang Zhang⁷

Affiliations

¹ Department of Emergency and Critical Disease, Songjiang Research Institute, Shanghai Key Laboratory of Emotions and Affective Disorders, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; State Key Laboratory of Cellular Stress Biology, School of Life Science, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, Fujian, China.
² Department of Emergency and Critical Disease, Songjiang Research Institute, Shanghai Key Laboratory of Emotions and Affective Disorders, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
³ Institute of Neuroscience, Key Laboratory of Molecular Neurobiology, Ministry of Education, Navy Military Medical University, Shanghai 200433, China.
⁴ School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361002, Fujian, China.
⁵ Engineering Research Centre of Molecular Diagnostics of the Ministry of Education, State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361002, Fujian, China.
⁶ State Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, Yunnan, China; School of Future Technology, University of Chinese Academy of Sciences, Beijing 101408, China.
⁷ Department of Emergency and Critical Disease, Songjiang Research Institute, Shanghai Key Laboratory of Emotions and Affective Disorders, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Institute of Neuroscience, Key Laboratory of Molecular Neurobiology, Ministry of Education, Navy Military Medical University, Shanghai 200433, China. Electronic address: lzhang@shsmu.edu.cn.

PMID: 41831443
DOI: 10.1016/j.neuron.2026.01.013

Abstract

Evolutionary adaptations provide a powerful lens for discovering fundamental regulators. By studying a Retsat variant (Q247R) found in high-altitude-adapted species, we reveal a central pathway governing CNS myelination and repair. Mice harboring this variant show reduced neonatal hypoxia-induced hypomyelination and exhibit enhanced remyelination in adulthood. The variant exhibits heightened enzymatic activity, driving increased neuronal production of all-trans-13,14-dihydroretinol (ATDR). By ruling out an intrinsic role in oligodendrocytes, we define this pathway as non-cell autonomous. ATDR is converted in neurons to all-trans-dihydroretinoic acid, which acts as a neuron-to-glia paracrine signal to activate the RXR-γ pathway in oligodendrocyte progenitor cells, thereby stimulating their differentiation and myelination. Administration of ATDR, a prodrug, potently promotes remyelination in multiple myelin injury models. Our work identifies Retsat and dihydroretinoids as pivotal regulators of white matter integrity and as a promising therapeutical avenue inspired by evolutionary genetics for white matter diseases.

Keywords: evolutionary adaptation; myelin; oligodendrocyte; white matter injury.