development of the four cardiac chambers, septum, and various valve components for outflow and inflow. In heart development, Tbx2 is up-regulated by BMP2 to stimulate atrioventricular development. The development of a Tbx2 knockout mouse model allowed for the determination of specific roles of Tbx2 in cardiac development, and scientists determined Tbx2 and Tbx3 to be redundant in much of heart development. Further, the use of these knockout models determined the significance of Tbx2 in the BMP signaling pathway for development of the atrioventricular canal, atrioventricular nodal phenotype, and atrioventricular cushion. The atrioventricular canal signaling cascade involves the atrial natriuretic factor gene (ANF). This gene is one of the first hallmarks of chamber formation in the developing myocardium. A small fragment within this gene can repress the promoter of cardiac troponin I (cTnI) selectively in the atrioventricular canal. T-box factor and NK2-homeobox factor binding element are involved in the repression of the atrioventricular canal without affecting its chamber activity. Tbx2 forms a complex with Nkx2.5 on the ANF gene to repress its promoter activity, so that the gene's expression is inhibited in the atrioventricular canal during chamber differentiation. The atrioventricular canal is also the origin of the atrioventricular nodal axis and helps eventually coordinate the beating heart. The role of Tbx2 in cushion formation in the developing heart is by working with Tbx3 to trigger a feed-forward loop with BMP2 for the coordinated development of these cushions. Tbx2 has also been found to temporally suppress the proliferation and differentiation a subset of the primary myocardial cells. Finally, during anterior brain development, BMP stimulates the expression of Tbx2, which suppresses FGF signaling. This suppression of FGF signaling further represses the expression of Flrt3, which is necessary for anterior brain development. Tbx2 has been shown to be a master regulator in the differentiation of inner and outer hair cells. Associated congenital defects It is known that Tbx2 functions in a dose-dependent manner; therefore, duplication or deletion of the region encompassing Tbx2 can cause various congenital defects, including: microcephaly, various ventricular-septal defects, and skeletal abnormalities. Some specific abnormalities are discussed further below. Mutations in TBX2 cause predisposition to hernias. Abnormalities of the digits During limb bud development, down-regulation of Tbx2 fails to inhibit Shh/FGF4 signaling; therefore, resulting in increased limb bud size and duplication of the 4th digit, polydactyly. Opposite this, when Tbx2 is over expressed or duplicated, limb buds are smaller and can