Abstract
Astrocyte elevated gene-1 (AEG-1) is a key regulatory factor of progression in multiple types of tumor and neurodegenerative disease development. AEG-1 is associated with glutamate excitotoxicity due to its reported function of repressing excitatory amino acid transporter 2 expression in astrocytes. Although the function of AEG-1 has been demonstrated in neurological disorders, such as Alzheimer's disease and amyotrophic lateral sclerosis, the underlying mechanism of neuronal AEG-1 function remains unclear. The aim of the present study was to clarify the function and related mechanism of AEG-1 in neurons. A stable AEG-1-deficient HT22 neuronal cell line was constructed using CRISPR/Cas9 gene-editing technology. Reverse transcription-quantitative PCR and western blotting were carried out to analyze the knockdown efficiency of AEG-1-deficient HT22 cell line. RNA Sanger sequencing analysis was performed in AEG-1-deficient HT22 cells and wild-type HT22 cells without knockout (KO). Results from RNA sequencing revealed that AEG-1 modulated neuronal morphology and development by regulating the expression of numerous genes, such as ubiquitin C, C-X-C motif chemokine ligand 1, MMP9, Notch1, neuropilin 1 and ephrin type-A receptor 4. In addition, AEG-1 deficiency impacted several signaling pathways by mediating cell survival differentiation, apoptosis, and migration; this included the TNF-α pathway, the NF-κB pathway, the MAPK signaling pathway, the Notch signaling pathway and Axon guidance. Downregulation in cellular ion homeostasis, including ion channel function and neurotransmitter release, were observed after knocking out AEG-1 expression. Collectively, the present study provides insights into AEG-1-dependent gene regulation and signaling pathway transduction in neurons. The results of the present study may be applied for improving the understanding of AEG-1-associated central nervous system diseases.