Tbx5, a member of the T-box transcription factor family, is primarily known for its role in cardiac and forelimb development [2]. In cardiac development, it is involved in multiple processes such as cardiomyocyte maturation, septation, patterning of the cardiac conduction system, and maintenance of mature cardiomyocyte function [2]. Mutations in Tbx5 are associated with Holt-Oram syndrome, which is characterized by congenital heart defects and preaxial radial ray upper limb defects [3,4].

Selective knockout (KO) of Tbx5 in the atrial working myocardium of neonatal mice showed that it is required to maintain atrial identity. Atrial Tbx5 inactivation downregulated atrial-specific gene expression and increased the expression of ventricular identity genes [1,5]. Genomic analysis revealed that 69% of control-enriched ATAC regions were bound by TBX5, suggesting these regions function as TBX5-dependent enhancers [1,5]. Also, 510 chromatin loops sensitive to TBX5 dosage were identified, with 74.8% (in one study) and 73.7% (in another) of control-enriched loops containing anchors in control-enriched ATAC regions [1,5]. Conditional knockdown of Tbx5 in Hh-receiving cells in a mouse model led to limb defects, indicating Tbx5 is required for digit identity and negatively regulates Hh-signaling activity [6].

In conclusion, Tbx5 is a key regulator in cardiac and forelimb development. Mouse models with Tbx5 KO or conditional knockdown have revealed its role in maintaining atrial identity and digit determination. Understanding its function provides insights into Holt-Oram syndrome and other related congenital heart and limb diseases [2,3,4,6].