Vgll2-KO Mouse

Vgll2, vestigial-like family member 2, is a skeletal-muscle-specific transcription co-factor. It plays a crucial role in coordinating mitochondrial function and contractility in skeletal muscle, being involved in muscle fiber type transition [2,5]. It also interacts with TEAD transcription factors via its Tondu motif and an Ω-loop, which is important in its function [4]. Genetic models, such as gene-deficient mice, are valuable for studying Vgll2.

In gene-deficient mice, Vgll2 is shown to be essential for fast-to-slow adaptation of skeletal muscle. Its deficiency leads to limited fiber type transition and down-regulation of genes related to lactate metabolism [2,5]. In zebrafish, Vgll2-NCOA2 fusion is sufficient to generate mesenchymal tumors mimicking human infantile rhabdomyosarcoma, indicating its role in tumorigenesis [1]. Homozygous truncating variants in VGLL2 in humans cause syngnathia, though this craniofacial anomaly is not seen in vgll2a mutant zebrafish or Vgll2 -/- mice [3].

In summary, Vgll2 is a key integrative regulator of mitochondrial function and contractility in skeletal muscle. Gene-knockout mouse models have revealed its significance in muscle adaptation processes. Its role in tumorigenesis and in causing human craniofacial malformations, as shown through various research models, provides important insights into related disease mechanisms [1,2,3,5].

References:

1. Watson, Sarah, LaVigne, Collette A, Xu, Lin, Amatruda, James F, Kendall, Genevieve C. 2023. VGLL2-NCOA2 leverages developmental programs for pediatric sarcomagenesis. In Cell reports, 42, 112013. doi:10.1016/j.celrep.2023.112013. https://pubmed.ncbi.nlm.nih.gov/36656711/

2. Honda, Masahiko, Inoue, Ryota, Nishiyama, Kuniyuki, Shirakawa, Jun, Okada, Hitoshi. 2024. Vgll2 as an integrative regulator of mitochondrial function and contractility specific to skeletal muscle. In Journal of cellular physiology, 239, e31436. doi:10.1002/jcp.31436. https://pubmed.ncbi.nlm.nih.gov/39286968/

3. Agostini, Valeria, Tessier, Aude, Djaziri, Nabila, Amiel, Jeanne, Gordon, Christopher T. 2023. Biallelic truncating variants in VGLL2 cause syngnathia in humans. In Journal of medical genetics, 60, 1084-1091. doi:10.1136/jmg-2022-109059. https://pubmed.ncbi.nlm.nih.gov/37666660/

4. Mesrouze, Yannick, Chène, Patrick. 2024. Study of the TEAD-binding domain of the VGLL1, VGLL2 and VGLL3 proteins from vertebrates. In Archives of biochemistry and biophysics, 760, 110136. doi:10.1016/j.abb.2024.110136. https://pubmed.ncbi.nlm.nih.gov/39182750/

5. Honda, Masahiko, Tsuchimochi, Hirotsugu, Hitachi, Keisuke, Ohno, Seiko. 2019. Transcriptional cofactor Vgll2 is required for functional adaptations of skeletal muscle induced by chronic overload. In Journal of cellular physiology, 234, 15809-15824. doi:10.1002/jcp.28239. https://pubmed.ncbi.nlm.nih.gov/30724341/