Transcription factor 21 (TCF21), also known as pod-1, capsuling, or epicardin, is a protein that in humans is encoded by the TCF21 gene on chromosome 6. It is ubiquitously expressed in many tissues and cell types and highly significantly expressed in lung and placenta. TCF21 is crucial for the development of a number of cell types during embryogenesis of the heart, lung, kidney, and spleen. TCF21 is also deregulated in several types of cancers, and thus known to function as a tumor suppressor. The TCF21 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease. Discovery TCF21 was discovered in 1998 when search for novel cell-type-specific bHLH proteins expressed in human and mouse kidneys by performing a search of the expressed sequence tag (EST) databases. Because the transcript they found was highly expressed in visceral glomerular epithelial cells (podocytes), TCF21 was initialled named Pod-1. Comparison of Pod-1 with previously characterized bHLH proteins identified Pod-1 as a novel member of a subfamily of bHLH proteins with important roles in mesodermal development. The chromosomal location of Pod-1 in the mouse was then determined using an interspecific backcross panel along with genomic southern blot analysis to identify restriction fragment length polymorphisms (RFLPs) between inbred mouse strains. Analysis showed Pod-1 to map to a region of mouse chromosome 10 that is syntenic with human chromosome 6q23-q24. The tissue distribution of Pod-1 was determined by hybridization of a human multiple tissue northern blot with a Pod-1 cDNA. A probe lacking the bHLH domain was used to minimize cross-reactivity along with high stringency hybridization and washing. Results showed that in humans and mice, Pod-1 was most highly expressed in the kidney, lung and heart, with selective expression at sites of epithelial-mesenchymal interaction in the kidney, lung, intestine and pancreas of developing mouse embryos. RNA in situ hybridization using 33P-labeled riboprobes was used to identify the cell types that expressed Pod-1 in the developing kidney and other tissues. This revealed Pod-1 expression in mesenchymal cells and podocytes, with expression coinciding with the onset of podocyte differentiation. It was found that expression of Pod-1 in embryonic kidney explants was inhibited through antisense oligonucleotides. This inhibition resulted in decreased mesenchymal cell condensation around the ureteric bud and a significant decrease in ureteric branching. Pod-1 was the first tissue-restricted bHLH protein to be identified in the developing kidney and tied to regulation of morphogenetic events.