CONTROLLED EXPRESSION OF TBX1 FUNCTION DURING PHARYNGEAL DEVELOPMENT: AN IMPROVED MODEL FOR DIGEORGE SYNDROME

DiGeorge syndrome (DGS) is a common genetic cause of heart defects. Patients often also have hypocalcemia (from parathyroid defects) and immune deficits (from thymic anomalies). One of the two copies of chromosome 22 is abnormally deleted in DGS patients, so that they are missing about 25 genes. Which one(s) of these causes DGS is presently still not clear. To better understand the genetics of DGS, a similar deletion has been made in the mouse by modifying its chromosome 16 so as to cause a deletion, called Df1, that causes the loss of about 18 genes which are identical to genes missing in DGS patients. Mice with the Df1 deletion show the same cardiovascular defects seen in DGS patients. Recently, researchers have uncovered Tbx1 as the gene responsible for the heart defects associated with the Df1 deletion. Loss of one copy of Tbx1 causes the same heart defects seen in mice with Df1 deletion and in patients with DGS. However, the other problems associated with DGS are not found in either mouse, making both incomplete models of the human disease. On the other hand, loss of both copies of Tbx1 severely disrupts development, and results in lack of thymus and parathyroids, and in heart defects that are similar to but more severe than those seen in the human syndrome. These findings suggest that Tbx1 has many important roles in development, but these roles cannot be studied with the mouse models available. The aim of this proposal is to "engineer" mutant mice in which the levels of Tbx1 can be controlled by administering particular drugs. This study will clarify when and where Tbx1 is required, and will shed light on processes that drive development of the organs affected in DGS, include the heart. The new mutant mice will be better models of DGS, helping to further understand the human disease.