Functional network and cross-system regulatory mechanisms of TBX4. (IMAGE)
Caption
This figure illustrates the multifaceted regulatory roles of TBX4 and its pathological associations across the respiratory, musculoskeletal, and other organ systems, as well as in tumorigenesis. In the respiratory system, TBX4 governs tracheobronchial cartilage formation, alveolar and bronchiolar branching morphogenesis, and lung tissue repair. Mutations or reduced expression are linked to pulmonary arterial hypertension (PAH), neonatal respiratory failure, and tracheal malformations. Within the musculoskeletal system, TBX4 regulates hindlimb initiation, soft tissue morphogenesis, and vascular network patterning, while heterozygous mutations or point mutations (e.g., rs3744448) are linked to stiff-person syndrome (SPS) and developmental dysplasia of the hip (DDH). In other systems, TBX4 contributes to craniofacial, cardiac, genital, and anorectal development, and modulates immune homeostasis via regulation of ELF4, RUNX3, and ZMIZ1. Dysregulation of TBX4 is implicated in conditions such as cleft lip/palate, isolated cleft palate, and genital system malformations. In cancer, TBX4 exhibits dual regulatory roles: low expression drives malignant progression in non-small cell lung cancer and pancreatic ductal adenocarcinoma, while high expression exerts tumor-suppressive effects in Wilms tumor and thyroid cancer, potentially mediated through epigenetic modifications (e.g., methylation) and lncRNA regulation (e.g., TTTY15/NME1 axis). At the molecular level, TBX4 orchestrates organ morphogenesis via the SOX9–FGF10–BMP pathway, mediates tissue repair through Wnt/β-catenin and RA signaling, and dynamically modulates the tumor microenvironment via non-coding RNAs (e.g., ocu-miR-29-5p). This integrative framework highlights TBX4's complex regulatory network, providing a systematic perspective on its roles in development, immunity, and disease pathogenesis.
Credit
Lin Yi, Li Zhou, Bianfei Shao, Tingxiu Xiang, Jingyi Tang
Usage Restrictions
Credit must be given to the creator. Only noncommercial uses of the work are permitted. No derivatives or adaptations of the work are permitted.
License
CC BY-NC-ND