| Although the Ca2+/calcineurin/NF-ATc pathway was first characterized in lymphocytes, it has become clear that this pathway functions broadly in mammalian development. Previous genetic inactivation of the components of this pathway in mice have illustrated that Ca2+/calcineurin/NF-ATc signaling is required for both lymphocyte and cardiovascular development; however, these studies have also revealed a measure of redundancy in calcineurin/NF-ATc signaling in vivo, since the observed phenotypes are often less severe than what is observed when the pathway is blocked pharmacologically. One way to genetically address the redundancy of this pathway is to target the common Cnb1 regulatory subunit of calcineurin in mice. Since germline inactivation of the gene encoding this subunit results in embryonic lethality, we generated mice in which the removal of Cnb1 function could be spatially and temporally controlled using the Cre/lox system. We show that disruption of Cnb1 function specifically in developing thymocytes results in a complete removal of calcineurin activity and disrupts thymocyte positive but not negative selection. These studies also reveal a novel cross-talk between the Ca2+/calcineurin/NF-ATc and Ras/MEK/ERK pathways. In addition, we examine the role of the Ca2+/calcineurin/NF-ATc pathway in cardiovascular development by specific inactivation of Cnb1 function in the endothelium. Comparison of the phenotype in these animals with those observed in a battery of germline Cnb1 and NF-ATc mutant and transgenic mice reveals that the Ca2+/calcineurin/NF-ATc pathway specifically and sequentially directs cardiac valve formation, first in the myocardium by local suppression of VEGF production, and then in the endocardium where it controls the development of cardiac valves by an as-yet-undefined mechanism. |
