Peer-reviewed article

Loss of med14 causes developmental malformations characteristic of VACTERL association by disrupting the Mediator complex.

Jingwen Liu, Xuelai Liu, Feifei Li, Yujie Wang, Liping Yang et al. · 24 Jul 2025

Abstract

MED14 is the largest subunit in the Mediator complex and plays a key role in regulating RNA polymerase II-mediated transcription, but its developmental function remains largely unknown. Here, we show that med14 is required for the proper formation of multi-organs, including the heart, pectoral fin, vertebrae, cloaca, and pronephros, most of which are derived from the mesoderm and are generally affected by VACTERL association, a syndrome with higher prevalence in males. Using this animal model, we further demonstrated that failures in cell fate decisions during organogenesis, but not in early mesoderm formation and subsequent medio-lateral patterning, were the cause of the multi-organ malformations. Importantly, we identified a novel missense mutation in the MED14 gene (p.Ile550Val) located on the X chromosome in a patient and his family, and neonatal mice carrying the corresponding mutation displayed diagnostic features of VACTERL association. Further investigation revealed that this mutation impairs the structural role of MED14 in the recruitment of specific subunits, such as MED7 and MED17, to the Mediator complex, thereby compromising the interaction between the Mediator complex and RNA polymerase II and decreasing the expression of a set of downstream genes required for the organogenesis of VACTERL-related systems. Taken together, our work uncovers an essential role of MED14 in fetal organogenesis and provides mechanistic insights into the connection between VACTERL association and the Mediator complex.