Deletion of Asrgl1 Leads to Photoreceptor Degeneration in Mice

Yu Zhou; Wanli Tian; Xiaoyan Jiang; Huining Yang; Zhilin Jiang; Xiao Li; Dan Jiang; Kuanxiang Sun; Yeming Yang; Wenjing Liu; Xianjun Zhu

doi:10.3389/fcell.2021.783547

Deletion of Asrgl1 Leads to Photoreceptor Degeneration in Mice

Front Cell Dev Biol. 2022 Jan 18:9:783547. doi: 10.3389/fcell.2021.783547. eCollection 2021.

Authors

Yu Zhou^{1

2}, Wanli Tian^{1

2}, Xiaoyan Jiang^{1

2}, Huining Yang^{1

2}, Zhilin Jiang^{1

2}, Xiao Li^{1

2}, Dan Jiang^{1

2}, Kuanxiang Sun^{1

2}, Yeming Yang^{1

2}, Wenjing Liu^{1

2}, Xianjun Zhu^{1

2

3}

Affiliations

¹ Sichuan Provincial Key Laboratory for Human Disease Gene Study, Department of Laboratory Medicine, Center for Medical Genetics, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
² Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China.
³ Department of Ophthalmology, First People's Hospital of Shangqiu, Shangqiu, China.

Abstract

The asparaginase and isoaspartyl peptidase 1 (ASRGL1) is an L-asparaginase and beta-aspartyl peptidase enzyme that may be involved in the formation of L-aspartate, a neurotransmitter that can operate as an excitatory neurotransmitter in some brain regions. Although variants in ASRGL1 have been reported in retinitis pigmentosa (RP) patients, the in vivo functions and mechanisms of ASRGL in RP remains unknown due to the lack of suitable disease models. To explore the role of ASRGL in RP, we generated an Asrgl1 knockout mouse model (Asrgl1 KO) using the CRISPR/Cas9 technique. Asrgl1 ablation in mice led to an attenuated electroretinogram (ERG) response around 8 months. The thickness of the outer nuclei layer (ONL) started to decrease around 9 months in Asrgl1 KO mice and gradually intensified at 12 and 15 months. Immunostaining revealed thinner inner segment (IS) and thinner outer segment (OS) as well as the progressive degeneration of rod and cone cells in Asrgl1 KO mice. One hundred forty-nine transcriptional differentially expressed genes (DEGs) were found by RNA-seq in Asrgl1 KO retina. These DEGs were linked to a number of biological processes that were considerably enriched, including gastrointestinal disease and organismal injury and abnormalities. By analysis of canonical pathways, glucocorticoid receptor signaling was the most significant canonical pathway altered in Asrgl1 KO retina. Several molecules, including NFE2L2, IL-4, Foxp3, and Fos, were in the central nodes of the interaction network in Asrgl1 KO retina. In summary, our study provided a knockout mouse model for a better understanding of the molecular mechanism for ASRGL1-related RP.

Keywords: RNA-seq; asparaginase and isoaspartyl peptidase 1; knockout mouse model; photoreceptor degeneration; retinitis pigmentosa.