Role of Elavl-like RNA-binding protein in retinal development and signal transduction

• Published in: Biochimica et biophysica acta. Molecular basis of disease 2025-01, Vol.1871 (1), p.167518, Article 167518
• Main Authors: Wutikeli, Huxitaer, Yu, Yao, Zhang, Tianlu, Cao, Jingjing, Nawy, Scott, Shen, Yin
• Format: Article
• Language: English
• Subjects: Amacrine cells; Amacrine Cells - cytology; Amacrine Cells - metabolism; Animals; Cell Differentiation; ELAV-Like Protein 2 - genetics; ELAV-Like Protein 2 - metabolism; ELAV-Like Protein 4 - genetics; ELAV-Like Protein 4 - metabolism; Elavl2; Elavl4; GABAb-receptors; Matrix Attachment Region Binding Proteins - genetics; Matrix Attachment Region Binding Proteins - metabolism; Mice; Mice, Knockout; Night Vision; Retina - cytology; Retina - metabolism; Retina development; Signal Transduction
• ISSN: 0925-4439; 1879-260X; 1879-260X
• DOI: 10.1016/j.bbadis.2024.167518

RNA-binding proteins (RBPs) play central roles in post-transcriptional gene regulation. However, the function of RBP in retinal progenitor cell differentiation and synaptic signal transmission are largely unexplored. Previously we have shown that Elavl2 regulates amacrine cell (AC) differentiation during retinogenesis, by directly binding to Nr4a2 and Barhl2. Elavl2 is expressed in early neuronal progenitors to mature neurons, and Elavl4 expression begins slightly later, during cortical neuron development as a paralog. Here, Retinal-specific Elavl2 and Elavl4 double knockout mice were made to further explore the role of Elavl2 and Elavl4 in retinal development and signal transduction. We disclose that Elavl4 binds to Satb1 to regulate Neurod1, then promoting retinal progenitor and amacrine cells differentiation. We were also surprised to find that Elavl2 interacted with GABAB receptors at the RNA and protein levels. In conclusion, Elavl2 and Elavl4 regulate amacrine cells differentiation through different pathways, leading to decreased scotopic vision. Our findings reveal the roles of Elavl2 and Elavl4 in retinal amacrine cells differentiation in modulating visual functions. A hypothetical model of Elavl2 and Elavl4 roles in ACs differentiation, GABAergic inhibitor synapse transmission, and visual function. Elavl2 binds to Nr4a2 and Barhl2 mRNA, and Elavl4 binds to Satb1 which is upstream of Neurod1 to regulate its expression, further modulating the differentiation of ACs, especially GABAergic and glycinergic ACs. Elavl2 may regulates the function of GABAergic inhibitory postsynaptic membrane receptors and the conduction of inhibitory signals by interacting with GABAB receptors. Therefore, ACs decreased in the retina combined with Elavl2 and Elavl4 deficiency, loss of ACs and GABAB receptors may affect retinal neurotransmission and cause induced ERG responses, visual acuity, and RGC spiking in the retina (Created with BioRender.com). [Display omitted] •RNA binding proteins Elavl2 and Elavl4 regulate amacrine cells differentiation, leading to decreased scotopic vision.•The GABAergic and Glycinergic amacrine cells in the retina of Elav2 and Elav4 knockout mice were significantly reduced.•Elavl2 binds to transcription factors Barhl2 and Nr4a2, while Elavl4 binds to transcription factor Satb1 to regulate Neurod1.•Elavl2 may participate in the inhibitory signal transmission process by regulating GABA BB-receptors