Fishing for T -box networks that regulate cardiac specifications and morphogenesis
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The heart is the first functioning organ to form in the developing embryo and defects during this process can lead to either embryonic lethality or congenital heart defects in humans, the leading cause of congenital anomalies. Formation of a functioning heart requires coordination of diverse processes including cell specification and differentiation and well as cellular migration and organ morphogenesis. Reflecting such complexity there are many different signaling pathways and transcription factor families that interact with each other to regulate cardiogenesis.;Proteins containing a T-box domain comprise one such family of transcription factors that have been shown to regulate many different steps of cardiac development. There are over 20 members of this family and they regulate formation of organs deriving from all three germ layers, namely mesoderm, endoderm, and ectoderm. Tbx1, 2, 3, 5, 18 and 20 are expressed in the developing heart and are essential for proper organogenesis. Mutations or deletions of some family members have been shown to cause cardiac defects in humans. T-box genes have been shown to interact with each other as well as with members of other families of transcription factors to generate a complex network that ultimately directs formation of the heart.;I utilized a loss-of-function strategy to dissect some of these interactions, making use of the zebrafish model, which is particularly amenable to this analysis since multiple genes can be knocked down simultaneously. In particular I focused on T-box interactions with the GATA family of transcription factors and their role in cardiac specification, as well as novel interactions within T-box family members themselves during cardiac morphogenesis. I discovered a novel phenotype arising from redundant function of two zebrafish T-box genes. Additionally my studies show that, just as temporal control of T-box expression is necessary for proper organ morphogenesis, tight control of spatial expression is also crucial. Closely related T-box genes can exert different functions depending on their precise expression domains within the same developing organ.