NFAT Signaling Probably Evolved in Vertebrates

Genomic studies indicate that NFAT signaling is a recent and perhaps vertebrate-specific pathway. Since the genes that encode the cytoplasmic subunits of NFAT transcription complexes (NFATc genes) are not present in the genomes of invertebrates this signaling pathway seems to have arisen in response to the specialized needs of vertebrate developmment, organogenesis and function. This signaling pathway appears concident in evolution with the recombinational immune system, a heart containing valves, a complexe vasculature, bone, cartilage and a variety of other organs. Recent data have indicated that these are precisely the systems where NFAT signaling is essential. The NFATc gene family appears in the genomes of vertebrates coincident with receptors such as the T cell receptor, B cell receptor, Neurotrophins, VEGF, Tie1, Tie 2 and other ligand-receptors that are found only in vertebrates. Using genetic approaches in mice we aim to understand the different roles of this pathway in development.

NFAT Signaling in Lymphocyte Development. Although much work indicates that NFAT signaling plays critical roles in the development and function of the immune system this requirement has been difficult to define genetically because of the redundancy among the genes encoding the three calcineurin regulatory and two catalytic subunits. In addition, the four genes that encode the cytoplasmic subunits of NFAT transcription complexes play vital roles in the development of the nervous system, heart, and vasculature that preclude simple approaches to understanding their function in the immune system. They are coexpressed in lymphocytes and we and others have been using multiple gene disruptions to learn how this pathway functions in T and B cell development as well as in the development of other cells of the immune system. Our present evidence indicates that this pathway is essential for the conversion of signals of graded intensity at the antigen receptor to an all or-none outcome (analogue-to-digital switch) in differentiation verus death. We would like to understand the signaling mechanisms underlying this switch.

NFAT signaling in the development of the heart and vascular systems. Mice with mutations in NFATC1, C3 or C4 die because of a requirement of this signaling pathway in the morphogenesis of the heart and vessels (Nature 1997, Cell 2001). In addition, Eric Olson and Jeff Molkentin have shown that calcineurin and NFATc4 are involved in the hypertrophic response to vascular insult, perhaps recapitulating a developmental response to cardiac growth signals. Ching-pin Chang (now a fellow in the Crabtree Lab) will continue work on the role of NFAT signaling in cardiovascular development in his lab.