Cardiovascular development: towards biomedical applicability

The heart of vertebrates is a unidirectional muscular pump that propels blood by means of synchronized contractions of two (fish) or four (mammals, birds) chambers, while the one-way valves prevent return flow [ 1 ]. In contrast to most other organs, the heart of higher vertebrates must function to supply the embryo and the extra embryonic membranes with blood from the moment it forms, pumping first in a peristaltic wave along the length of the primitive heart tube, before ballooning, looping and transforming into the complex four-chambered heart with its regular paced beat contraction. To accomplish this, the morphogenetic and functional requirements of the heart have been integrated into a perfectly coordinated genetic program underlying heart formation. Several key transcription factors involved in this genetic program have been identified, including Nkx2-5 and members of the Mef, Gata, Hand, Iroquois, Forkhead and T-box families of factors [ 2 , 3 ]. Although functional requirement of these factors has been demonstrated, their precise functions and interactions during cardiac morphogenesis have yet to be defined satisfactorily. Although a few early studies made mention of T-box factor genes expressed in the heart [ 4 , 5 ], it was the discovery that mutations in T-box factor TBX5 lead to Holt-Oram syndrome, a disease associated with congenital heart defects of differing severities, that initiated a series of studies to unravel the function of this family of transcription factors in heart development [ 6 , 7 ]. The T-box family presently counts 17 members in mouse and humans [ 8 ]. Members of the Tbx1 subfamily, Tbx1, Tbx18 and Tbx20 , and of the Tbx2 subfamily, Tbx2, Tbx3 and Tbx5 , have all been found to play specific roles in heart development [ 8 – 10 ].