Vgll2, vestigial-like family member 2, is a skeletal-muscle-specific transcription co-factor. It is involved in coordinating mitochondrial function and contractility in skeletal muscle, playing a role in muscle fiber type transition, mitochondrial mass increase, and oxidative capacity enhancement [2,5]. It also participates in the Hippo pathway-related but YAP/TAZ-independent tumorigenesis when forming fusion proteins with TEAD1 or NCOA2 [3]. Genetic models like zebrafish and mice are valuable for studying its functions.

In mice, Vgll2 deficiency leads to limited fiber type transition and down-regulation of genes related to lactate metabolism during chronic overload, indicating its essential role in skeletal muscle functional adaptation to chronic overload [5]. In zebrafish, the VGLL2-NCOA2 fusion can generate mesenchymal tumors mimicking human infantile rhabdomyosarcoma, revealing its oncogenic role in pediatric sarcomagenesis [1]. Biallelic truncating variants in VGLL2 cause syngnathia in humans, though no craniofacial anomalies were observed in vgll2a or vgll4l homozygous mutant zebrafish or Vgll2 -/- mice [4].

In summary, Vgll2 is a crucial integrator of mitochondrial function and contractility in skeletal muscle. Its study using gene-knockout models in mice and zebrafish has provided insights into its roles in muscle adaptation, pediatric sarcomagenesis, and craniofacial development in humans. These findings contribute to understanding the underlying mechanisms of related biological processes and diseases.