Heterozygous mutations of Tbx3 caused decreased branching morphogenesis in the first three pairs of mammary glands, but had no significant impact on the fourth and fifth pairs of mammary glands. In 18. 5 day old Tbx3 heterozygous embryos, 75% of the first pair of mammary glands was missing with no nipple or ductal tree formation while the second pair of mammary selleck chem MG132 glands was affected to a lesser extent. Although these studies suggest that Tbx3 regulates murine mam mary glands differently, we found that over expression of TBX3 promotes accelerated mammary gland develop ment in both the first and fourth mammary glands as well as the second, third and fifth mammary glands. Research has solidified a role for Tbx3 in the early development of the mammary gland.

Tbx3 homozygous mutant mice results in mammary gland hypoplasia while heterozygous mutations of Tbx3 caused decreased branching morphogenesis in mammary glands. Our research complements these previous studies show ing that TBX3 over expression within the mammary glands causes hyperplasia, promoting increased second ary and tertiary branching as well as accelerated ductal elongation. It is also important to discuss that we have over expressed human TBX3 within the mammary glands of mice. It has been shown that human TBX3 and mouse Tbx3 are 97% homologous at the protein level. Our group and others have demonstrated that human TBX3 is functional in mouse cells. Furthermore, aTbx3 knockout mouse model was able to recapitulate the phenotype seen in humans with Ulnar Mammary Syndrome. In a study performed by Papaioannou et al.

a mutation in the mouse Tbx3 gene that Drug_discovery closely corresponds to truncation mutations seen in some individuals with UMS resulted in a deficiency in mammary placode induction and the absence or reduc tion of mammary buds in mutant embryos, correspond ing to the mammary gland hypoplasia seen in patients with UMS. Moreover, the deficiency in the development of limb elements in individuals with UMS was also reflected in limb abnormalities in the Tbx3 mutant mice. Mutant mice had deformities in the forelimb digits, foot and fibula resulting from a failure in the development of posterior limb elements. This study exemplifies that the Tbx3 protein plays a similar role in the development of the mammary glands in both human and mice. The mechanism by which TBX3 over expression promotes hyperplasia in mammary glands needs to be elucidated.

Using an Edu cell proliferation assay, we showed that over expression of TBX3 resulted in a dramatic increase in cell proliferation within the mammary glands of pregnant doxycycline induced dou ble transgenic mice at 10. 5 dpc. Although cell proliferation was not directly quantified for the merely other developmental time points, the similarity in the observed accelerated mammary gland development suggests that the increase in cell proliferation at 10.