Deletion of Asrgl1 Leads to Photoreceptor Degeneration in Mice.
Deletion of Asrgl1 Leads to Photoreceptor Degeneration in Mice.
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DOI：
10.3389/fcell.2021.783547
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发表时间：
2021
影响因子：
5.5
通讯作者：
Zhu X
中科院分区：
文献类型：
--
作者：
Zhou Y;Tian W;Jiang X;Yang H;Jiang Z;Li X;Jiang D;Sun K;Yang Y;Liu W;Zhu X
门冬酰胺酶和异门冬氨酸肽酶1是一种L天冬氨酰胺酶和β-天冬氨酸肽酶，可能参与了L-天冬氨酸的形成，天冬氨酸是一种神经递质，在大脑的某些区域起到兴奋性神经递质的作用。尽管ASRGL1在视网膜色素变性(RP)患者中的变异已有报道，但由于缺乏合适的疾病模型，ASRGL1在RP中的体内功能和机制仍不清楚。为了探讨ASRGL在RP中的作用，我们使用CRISPR/Cas9技术建立了ASRGL1基因敲除小鼠模型(ASRGL1KO)。在小鼠中，ASRGL1消融导致大约8个月的视网膜电信号(ERG)反应减弱。在ASRGL1 KO小鼠中，外核层厚度在9个月左右开始减少，12和15个月时逐渐加强。免疫组织化学染色显示ASRGL1KO小鼠内节(IS)和外节(OS)变薄，视杆细胞和视锥细胞进行性变性。RNAseq分析发现ASRGL1KO视网膜中有149个转录差异表达基因(Deg)。这些DEG与许多相当丰富的生物过程有关，包括胃肠道疾病和器官损伤和异常。通过对典型通路的分析，糖皮质激素受体信号通路是ASRGL1 KO视网膜改变最显著的典型通路。包括NFE2L2、IL-4、Foxp3和Fos在内的几个分子位于ASRGL1 KO视网膜相互作用网络的中央节点。总之，我们的研究为更好地理解ASRGL1相关RP的分子机制提供了一个基因敲除小鼠模型。
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.
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影响因子：
2.3
作者：
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影响因子：
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