Elavl2-KO Mouse

Elavl2, also known as embryonic lethal abnormal vision Drosophila homolog-like 2, is an RNA-binding protein. It is involved in multiple biological processes, regulating mRNA stability and alternative splicing, and plays a role in pathways related to cell differentiation, development, and disease-associated processes [1-9]. Genetic models, such as gene knockout (KO) and conditional knockout (CKO) mouse models, are valuable for studying its functions.

In glioblastoma, Elavl2 loss promotes aggressive mesenchymal transition. Transcriptomic analysis showed its loss is associated with EMT-related genes, chemo-resistance, and poor survival in patients. Elavl2 binds to transcripts of EMT-inhibitory molecules, modulating their mRNA stability, potentially via an m6A-dependent mechanism [1].

In the retina, retina-specific ablation of Elavl2 using the Cre-loxP system led to the loss of amacrine cells (ACs), increased spontaneous activities of retinal ganglion cells (RGCs), decreased electroretinogram (ERG) responses, and reduced visual acuity, indicating its role in ACs differentiation during retinogenesis [2].

Elavl2 knockout females are infertile due to defective primordial follicle formation in mouse ovaries. It directs the assembly of P-body-like granules by promoting DDX6 translation, which is crucial for primordial follicle formation [3].

Depleting Elavl2 in wild-type neurons led to global shortening of 3'UTR length, reduced immunostimulatory dsRNA levels, and increased susceptibility to virus infections. In ADAR1 knockout neurons, depleting Elavl2 prolonged neuron survival by reducing dsRNA-mediated toxic inflammation [4].

In human neurons, haploinsufficient levels of Elavl2 identified networks of differentially expressed and alternatively spliced genes, including autism-relevant genes [5].

In spermatogonia, knockdown of Elavl2 in cell lines inhibited proliferation and promoted apoptosis, and it interacted with DAZL [6].

In a hypoxia-induced pulmonary hypertension mouse model, DHA treatment promoted Elavl2 expression, inhibiting the proliferation and migration of pulmonary artery smooth muscle cells [7].

RNAi knockdown of Elavl2 in bees demonstrated its requirement for learning and memory [8].

In ovarian cancer cells, gene silencing of Elavl2/4 prevented up-regulation of glycolysis-related enzymes and sensitized cells to anticancer agents under hypoglycemic conditions [9].

In conclusion, Elavl2 is essential for multiple biological processes. KO/CKO mouse models and other loss-of-function experiments have revealed its role in diseases such as glioblastoma, pulmonary hypertension, and potentially in neurodegenerative and neuroinflammatory diseases, as well as in normal physiological processes like retinal development, ovarian follicle formation, spermatogonia regulation, and learning and memory in bees. These findings contribute to our understanding of disease mechanisms and potential therapeutic targets.

References:

1. Kim, Yona, You, Ji Hyeon, Ryu, Yeonjoo, Park, Sung-Hye, Paek, Sun Ha. 2024. ELAVL2 loss promotes aggressive mesenchymal transition in glioblastoma. In NPJ precision oncology, 8, 79. doi:10.1038/s41698-024-00566-1. https://pubmed.ncbi.nlm.nih.gov/38548861/

2. Wu, Mengjuan, Deng, Qinqin, Lei, Xinlan, Du, Yuxin, Shen, Yin. . Elavl2 Regulates Retinal Function Via Modulating the Differentiation of Amacrine Cells Subtype. In Investigative ophthalmology & visual science, 62, 1. doi:10.1167/iovs.62.7.1. https://pubmed.ncbi.nlm.nih.gov/34061953/

3. Kato, Yuzuru, Iwamori, Tokuko, Ninomiya, Youichirou, Sato, Mikiko, Saga, Yumiko. 2019. ELAVL2-directed RNA regulatory network drives the formation of quiescent primordial follicles. In EMBO reports, 20, e48251. doi:10.15252/embr.201948251. https://pubmed.ncbi.nlm.nih.gov/31657143/

4. Dorrity, Tyler J, Shin, Heegwon, Wiegand, Kenenni A, Wichterle, Hynek, Chung, Hachung. 2023. Long 3'UTRs predispose neurons to inflammation by promoting immunostimulatory double-stranded RNA formation. In Science immunology, 8, eadg2979. doi:10.1126/sciimmunol.adg2979. https://pubmed.ncbi.nlm.nih.gov/37862432/

5. Berto, Stefano, Usui, Noriyoshi, Konopka, Genevieve, Fogel, Brent L. 2016. ELAVL2-regulated transcriptional and splicing networks in human neurons link neurodevelopment and autism. In Human molecular genetics, 25, 2451-2464. doi:. https://pubmed.ncbi.nlm.nih.gov/27260404/

6. Yang, Chao, Yao, Chencheng, Ji, Zhiyong, Zhou, Zhi, Li, Zheng. 2021. RNA-binding protein ELAVL2 plays post-transcriptional roles in the regulation of spermatogonia proliferation and apoptosis. In Cell proliferation, 54, e13098. doi:10.1111/cpr.13098. https://pubmed.ncbi.nlm.nih.gov/34296486/

7. Cai, Haijian, Fan, Shiqian, Cai, Luqiong, Huang, Xiaoying, Wang, Liangxing. 2022. Dihydroartemisinin Attenuates Hypoxia-Induced Pulmonary Hypertension Through the ELAVL2/miR-503/PI3K/AKT Axis. In Journal of cardiovascular pharmacology, 80, 95-109. doi:10.1097/FJC.0000000000001271. https://pubmed.ncbi.nlm.nih.gov/35512032/

8. Ustaoglu, Pinar, Gill, Jatinder Kaur, Doubovetzky, Nicolas, Devaud, Jean-Marc, Soller, Matthias. 2021. Dynamically expressed single ELAV/Hu orthologue elavl2 of bees is required for learning and memory. In Communications biology, 4, 1234. doi:10.1038/s42003-021-02763-1. https://pubmed.ncbi.nlm.nih.gov/34711922/

9. Park, Ga Bin, Jeong, Jee-Yeong, Choi, Sangbong, Yoon, Yoo Sang, Kim, Daejin. . Glucose deprivation enhances resistance to paclitaxel via ELAVL2/4-mediated modification of glycolysis in ovarian cancer cells. In Anti-cancer drugs, 33, e370-e380. doi:10.1097/CAD.0000000000001215. https://pubmed.ncbi.nlm.nih.gov/34419957/