Loss of Arid1a Promotes Neuronal Survival Following Optic Nerve Injury.

Xue-Qi Peng,Shang-Kun Dai,Zhao-Qian Teng,Chang-Ping Li,Shu-Guang Yang,Pei-Pei Liu,Hong-Zhen Du,Chang-Mei Liu,Zhi-Meng Wang

doi:10.3389/fncel.2020.00131

Abstract

Trauma or neurodegenerative diseases trigger the retrograde death of retinal ganglion cells (RGCs), causing an irreversible functional loss. AT-rich interaction domain 1A (ARID1A), a subunit of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex, has been shown to play crucial roles in cell homeostasis and tissue regeneration. However, its function in adult RGC regeneration remains elusive. Here, we show that optic nerve injury induces dynamic changes of Arid1a expression. Importantly, deleting Arid1a in mice dramatically promotes RGC survival, but insignificantly impacts axon regeneration after optic nerve injury. Next, joint profiling of transcripts and accessible chromatin in mature RGCs reveals that Arid1a regulates several genes involved in apoptosis and JAK/STAT signaling pathway. Thus, our findings suggest modulation of Arid1a as a potential therapeutic strategy to promote RGC neuroprotection after damage.

Highlights

Optic nerve trauma or optic neuropathies typically lead to axon damage, progressive loss of retinal ganglion cells (RGCs), and even irreversible visual function deficits (Crair and Mason, 2016; Benowitz et al, 2017)
The results from quantitative real-time PCR analysis showed mRNA levels of Arid1a dramatically decreased after SNI compared to the control group (Supplementary Figure S1A)
Double immunostaining of dorsal root ganglion (DRG) sections with antibodies against AT-rich interaction domain 1A (ARID1A) and Tuj1 confirmed that the protein levels of Arid1a gradually decreased in both cytoplasm and nucleus of DRGs after SNI (Supplementary Figures S1B–D), suggesting that both ARID1A protein synthesis and ARID1A protein transportation to the nucleus were reduced in DRG neurons after axonal injury

Summary

Introduction

Optic nerve trauma (e.g., various cranial and orbital injuries) or optic neuropathies (e.g., glaucoma and ischemia) typically lead to axon damage, progressive loss of retinal ganglion cells (RGCs), and even irreversible visual function deficits (Crair and Mason, 2016; Benowitz et al, 2017). Like most other neurons in the central nervous system (CNS), mature RGCs fail to regenerate their axons after optic nerve injury, due to the extrinsic environment inhibitory elements and the diminished intrinsic regenerative capacity (He and Jin, 2016; Laha et al, 2017). Recent studies have shown that adult RGCs can regain the intrinsic ability to support axon regeneration after optic nerve injury by manipulating reprogramming factors, such as Klf, c-myc, and Lin, etc. Combinatorial approaches via modulating multiple independent pathways have been shown to promote injured axons to regenerate beyond the optic chiasm into the brain and reform functional synapses with their original targets (Lim et al, 2016; Goulart et al, 2018). Visual stimulation/RHEB1 overexpression led to regenerating axons back to almost all the correct targets. Synaptic reconnections partially restored optomotor response but not rescued pupil response, depth perception, visual fear response, suggesting that insufficient numbers of regenerating axons projection to the correct

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