Functional optic tract rewiring via subtype- and target-specific axonal regeneration and presynaptic activity enhancement

Xin Zhang; Chao Yang; Chengle Zhang; Junqiang Wu; Xiang Zhang; Jiayang Gao; Xuejie Wang; Leung Ting Chan; Yiren Zhou; Yujun Chen; Sindy Sing Ting Tam; Shuhang Chen; Yuqian Ma; Wing-Ho Yung; Liting Duan; Liwen Jiang; Yiwen Wang; Kai Liu

doi:10.1038/s41467-025-57445-x

Functional optic tract rewiring via subtype- and target-specific axonal regeneration and presynaptic activity enhancement

Xin Zhang (Co-first Author)
, Chao Yang (Co-first Author)
, Chengle Zhang (Co-first Author)
, Junqiang Wu
, Xiang Zhang
, Jiayang Gao
, Xuejie Wang
, Leung Ting Chan
, Yiren Zhou
, Yujun Chen
, Sindy Sing Ting Tam
, Shuhang Chen
, Yuqian Ma
, Wing-Ho Yung
, Liting Duan
, Liwen Jiang
, Yiwen Wang
, Kai Liu^*

^*Corresponding author for this work

Department of Neuroscience

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

5 Citations (Scopus)

104 Downloads (CityUHK Scholars)

Abstract

Mechanisms underlying functional axonal rewiring after adult mammalian central nervous system (CNS) injuries remain unclear partially due to limited models. Here we develop a mouse intracranial pre–olivary pretectal nucleus (OPN) optic tract injury model and demonstrate that Pten/Socs3 knockout and CNTF expression in retinal ganglion cells (RGCs) promotes optic tract regeneration and OPN reinnervation. Revealed by transmission electron microscopy, trans-synaptic labeling, and electrophysiology, functional synapses are formed in OPN mainly by intrinsically photosensitive RGCs, thereby partially restoring the pupillary light reflex (PLR). Moreover, combining with Lipin1 knockdown accelerates the recovery and achieves functional reconnection after chronic injury. PLR can be further boosted by increasing RGC photosensitivity with melanopsin overexpression, and it can also be enhanced by treatment of a voltage-gated calcium channel modulator to augment presynaptic release. These findings highlight the importance of neuronal types and presynaptic activity for functional reconnection after CNS injuries. © The Author(s) 2025.

Original language	English
Article number	2174
Journal	Nature Communications
Volume	16
Online published	4 Mar 2025
DOIs	https://doi.org/10.1038/s41467-025-57445-x
Publication status	Published - 2025

Funding

This study was supported by grants from the Hong Kong Research Grant Council (AoE/M-604/16, C6034-21G, T13-602/21N, 16102524, JLFS/M-604/24 to K.L., C4002-21EF, C4014-23G, CRS_CUHK405/23 to L.J., C4001-22Y to L.D., and PDFS2223-6S04 to C.Y.), Innovation and Technology Commission (ITCPD/17-9), Hong Kong Center for Neurodegenerative Diseases InnoHK of Hong Kong SAR, National Natural Science Foundation of China (82171384), Guangzhou Key Projects of Brain Science and Brain-Like Intelligence Technology (20200730009), Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions (2019SHIBS0001), Nan Fung Life Sciences to KL.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Publisher's Copyright Statement

This full text is made available under CC-BY 4.0. https://creativecommons.org/licenses/by/4.0/

RGC Funding Information

RGC-funded

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10.1038/s41467-025-57445-x

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Zhang, X., Yang, C., Zhang, C., Wu, J., Zhang, X., Gao, J., Wang, X., Chan, L. T., Zhou, Y., Chen, Y., Tam, S. S. T., Chen, S., Ma, Y., Yung, W.-H., Duan, L., Jiang, L., Wang, Y., & Liu, K. (2025). Functional optic tract rewiring via subtype- and target-specific axonal regeneration and presynaptic activity enhancement. Nature Communications, 16, Article 2174. https://doi.org/10.1038/s41467-025-57445-x

@article{6ff23a68dd184df4ae79600ac2c64045,

title = "Functional optic tract rewiring via subtype- and target-specific axonal regeneration and presynaptic activity enhancement",

abstract = "Mechanisms underlying functional axonal rewiring after adult mammalian central nervous system (CNS) injuries remain unclear partially due to limited models. Here we develop a mouse intracranial pre–olivary pretectal nucleus (OPN) optic tract injury model and demonstrate that Pten/Socs3 knockout and CNTF expression in retinal ganglion cells (RGCs) promotes optic tract regeneration and OPN reinnervation. Revealed by transmission electron microscopy, trans-synaptic labeling, and electrophysiology, functional synapses are formed in OPN mainly by intrinsically photosensitive RGCs, thereby partially restoring the pupillary light reflex (PLR). Moreover, combining with Lipin1 knockdown accelerates the recovery and achieves functional reconnection after chronic injury. PLR can be further boosted by increasing RGC photosensitivity with melanopsin overexpression, and it can also be enhanced by treatment of a voltage-gated calcium channel modulator to augment presynaptic release. These findings highlight the importance of neuronal types and presynaptic activity for functional reconnection after CNS injuries. {\textcopyright} The Author(s) 2025.",

author = "Xin Zhang and Chao Yang and Chengle Zhang and Junqiang Wu and Xiang Zhang and Jiayang Gao and Xuejie Wang and Chan, \{Leung Ting\} and Yiren Zhou and Yujun Chen and Tam, \{Sindy Sing Ting\} and Shuhang Chen and Yuqian Ma and Wing-Ho Yung and Liting Duan and Liwen Jiang and Yiwen Wang and Kai Liu",

year = "2025",

doi = "10.1038/s41467-025-57445-x",

language = "English",

volume = "16",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Springer Nature",

}

Zhang, X, Yang, C, Zhang, C, Wu, J, Zhang, X, Gao, J, Wang, X, Chan, LT, Zhou, Y, Chen, Y, Tam, SST, Chen, S, Ma, Y, Yung, W-H, Duan, L, Jiang, L, Wang, Y & Liu, K 2025, 'Functional optic tract rewiring via subtype- and target-specific axonal regeneration and presynaptic activity enhancement', Nature Communications, vol. 16, 2174. https://doi.org/10.1038/s41467-025-57445-x

Functional optic tract rewiring via subtype- and target-specific axonal regeneration and presynaptic activity enhancement. / Zhang, Xin (Co-first Author); Yang, Chao (Co-first Author); Zhang, Chengle (Co-first Author) et al.
In: Nature Communications, Vol. 16, 2174, 2025.

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

TY - JOUR

T1 - Functional optic tract rewiring via subtype- and target-specific axonal regeneration and presynaptic activity enhancement

AU - Zhang, Xin

AU - Yang, Chao

AU - Zhang, Chengle

AU - Wu, Junqiang

AU - Zhang, Xiang

AU - Gao, Jiayang

AU - Wang, Xuejie

AU - Chan, Leung Ting

AU - Zhou, Yiren

AU - Chen, Yujun

AU - Tam, Sindy Sing Ting

AU - Chen, Shuhang

AU - Ma, Yuqian

AU - Yung, Wing-Ho

AU - Duan, Liting

AU - Jiang, Liwen

AU - Wang, Yiwen

AU - Liu, Kai

PY - 2025

Y1 - 2025

N2 - Mechanisms underlying functional axonal rewiring after adult mammalian central nervous system (CNS) injuries remain unclear partially due to limited models. Here we develop a mouse intracranial pre–olivary pretectal nucleus (OPN) optic tract injury model and demonstrate that Pten/Socs3 knockout and CNTF expression in retinal ganglion cells (RGCs) promotes optic tract regeneration and OPN reinnervation. Revealed by transmission electron microscopy, trans-synaptic labeling, and electrophysiology, functional synapses are formed in OPN mainly by intrinsically photosensitive RGCs, thereby partially restoring the pupillary light reflex (PLR). Moreover, combining with Lipin1 knockdown accelerates the recovery and achieves functional reconnection after chronic injury. PLR can be further boosted by increasing RGC photosensitivity with melanopsin overexpression, and it can also be enhanced by treatment of a voltage-gated calcium channel modulator to augment presynaptic release. These findings highlight the importance of neuronal types and presynaptic activity for functional reconnection after CNS injuries. © The Author(s) 2025.

AB - Mechanisms underlying functional axonal rewiring after adult mammalian central nervous system (CNS) injuries remain unclear partially due to limited models. Here we develop a mouse intracranial pre–olivary pretectal nucleus (OPN) optic tract injury model and demonstrate that Pten/Socs3 knockout and CNTF expression in retinal ganglion cells (RGCs) promotes optic tract regeneration and OPN reinnervation. Revealed by transmission electron microscopy, trans-synaptic labeling, and electrophysiology, functional synapses are formed in OPN mainly by intrinsically photosensitive RGCs, thereby partially restoring the pupillary light reflex (PLR). Moreover, combining with Lipin1 knockdown accelerates the recovery and achieves functional reconnection after chronic injury. PLR can be further boosted by increasing RGC photosensitivity with melanopsin overexpression, and it can also be enhanced by treatment of a voltage-gated calcium channel modulator to augment presynaptic release. These findings highlight the importance of neuronal types and presynaptic activity for functional reconnection after CNS injuries. © The Author(s) 2025.

UR - https://www.scopus.com/pages/publications/86000091245

UR - https://www.scopus.com/record/pubmetrics.uri?eid=2-s2.0-86000091245&origin=recordpage

U2 - 10.1038/s41467-025-57445-x

DO - 10.1038/s41467-025-57445-x

M3 - RGC 21 - Publication in refereed journal

C2 - 40038284

SN - 2041-1723

VL - 16

JO - Nature Communications

JF - Nature Communications

M1 - 2174

ER -

Functional optic tract rewiring via subtype- and target-specific axonal regeneration and presynaptic activity enhancement

Abstract

Funding

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CRF-ExtU-Lead: Axon Regeneration-Mediated Functional Recovery by Regulating Intrinsic Mechanisms and Neuronal Activity

AoE(UGC)-ExtU-Lead: Cellular Mechanisms of Synaptic Functions and Plasticity in Health and Neurodegenerative Diseases

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