The regulation of cardiac cell proliferation and survival during vertebrate development

The formation of organs during development requires that cell proliferation occur in a coordinated fashion. Furthermore, mis-regulation of the cell cycle during adulthood is associated with cancer and other human diseases. The molecular pathways that govern the eukaryotic cell cycle have been extensively studied, however the mechanisms by which the cell cycle is regulated in a tissue specific manner during development are not well understood. In this work, we explore the regulation of cell proliferation within the developing heart, as well as the maintenance of proliferating cardiac progenitor cells.; The T-box transcription factor TBX5 is expressed within the developing heart and is required for heart morphogenesis in vertebrates. Additionally, mutations to TBX5 have been associated with the human congenital heart defect Holt-Oram syndrome. Despite the evolutionarily conserved role for TBX5 in heart development, the precise cellular requirement for TBX5 has not been defined. We show that one of the earliest defects in the TBX5-depleted Xenopus embryos is a reduction in cardiac cell number due to a decrease in mitotic index. We have further demonstrated that TBX5 is both necessary and sufficient to control cardiac cell cycle progression, and that depleting TBX5 leads to arrest in late G1 or early S-phase of the cell cycle. In this way, TBX5 is required to establish cardiac morphology during development.; Finally we have identified a requirement for the tyrosine phosphatase SHP-2 in the maintenance of proliferating cardiac progenitor cells downstream of FGF signaling. These studies show that SHP-2 is required for the maintenance of cardiac precursors, and that in the absence of SHP-2 activity, there is an increase in programmed cell death specifically in the cardiac precursor cells and pharyngeal mesoderm. When SHP-2 activity is inhibited at a later stage, when many cells have exited the cell cycle, cardiac differentation is able to proceed, however the number of proliferating cells within the heart is substantially reduced. These data suggest a specific requirement for SHP-2 in the survival of proliferating cardiac progenitor cells.