VGLL3, vestigial-like family member 3, is a transcriptional co-factor for the TEA-domain transcription factor (TEAD) family. It is involved in multiple biological processes and associated with various pathways. In the Hippo signaling network, it controls myogenesis. It also intersects with other pathways relevant to immune-metabolic regulation, DNA damage response, and mechanosensation, highlighting its overall biological importance. Genetic models, such as knockout (KO) mouse models, are valuable for studying its functions [3,4].

In cardiac fibrosis, VGLL3-deficient mice show significantly attenuated fibrosis after myocardial infarction, with increased miR-29b expression, revealing its role in promoting collagen production by myofibroblasts through a novel mechanosensitive pathway [1]. In DNA damage response, VGLL3 depletion impairs homologous recombination efficiency and increases cellular sensitivity to chemotherapeutic drugs, as it plays an unexpected role in this process distinct from its transcriptional co-factor function [2]. In slow-twitch muscle differentiation, VGLL3 promotes this process in C2C12 myocytes, and its protein degradation switches TEAD co-factors, suggesting a role in muscle fiber-type specification [3].

In conclusion, VGLL3 plays essential roles in multiple biological processes including cardiac fibrosis, DNA damage response, and muscle differentiation. Studies using KO mouse models have significantly contributed to understanding its role in these processes, providing potential therapeutic targets for related diseases such as tissue fibrosis and improving the understanding of DNA damage-related cancer therapies.

References:

1. Horii, Yuma, Matsuda, Shoichi, Toyota, Chikashi, Kosako, Hidetaka, Nakaya, Michio. 2023. VGLL3 is a mechanosensitive protein that promotes cardiac fibrosis through liquid-liquid phase separation. In Nature communications, 14, 550. doi:10.1038/s41467-023-36189-6. https://pubmed.ncbi.nlm.nih.gov/36754961/

2. Wu, Wei, Fan, Zhenzhen, Fu, Hui, Tang, Tie-Shan, Guo, Caixia. 2024. VGLL3 modulates chemosensitivity through promoting DNA double-strand break repair. In Science advances, 10, eadr2643. doi:10.1126/sciadv.adr2643. https://pubmed.ncbi.nlm.nih.gov/39383226/

3. Takakura, Yuki, Suzuki, Takayuki, Hirai, Naoto, Takano, Hiroyuki, Yamaguchi, Noritaka. 2023. VGLL3 confers slow-twitch muscle differentiation via PGC-1α expression in C2C12 myocytes. In Biochemical and biophysical research communications, 669, 30-37. doi:10.1016/j.bbrc.2023.05.073. https://pubmed.ncbi.nlm.nih.gov/37262950/

4. Figeac, Nicolas, Mohamed, Abdalla D, Sun, Congshan, Zammit, Peter S, Wackerhage, Henning. 2019. VGLL3 operates via TEAD1, TEAD3 and TEAD4 to influence myogenesis in skeletal muscle. In Journal of cell science, 132, . doi:10.1242/jcs.225946. https://pubmed.ncbi.nlm.nih.gov/31138678/