Role of the NF-ATc transcription factor in morphogenesis of cardiac valves and septum

In lymphocytes, the expression of early immune response genes is regulated by NF-AT transcription factors, which translocate to the nucleus after dephosphorylation by the Ca2+-dependent phosphatase, calcineurin. We report here that mice bearing a disruption in the NF-ATc gene fail to develop normal cardiac valves and septa and die of circulatory failure before day 14.5 of development. NF-ATc is first expressed in the heart at day 7.5, and is restricted to the endocardium, a specialized endothelium that gives rise to the valves and septum. Within the endocardium, specific inductive events appear to activate NF-ATc: it is localized to the nucleus only in endocardial cells that are adjacent to the interface with the cardiac jelly and myocardium, which are thought to give the inductive stimulus to the valve primordia. Treatment of wild-type embryos with FK506, a specific calcineurin inhibitor, prevents nuclear localization of NF-ATc. These data indicate that the Ca2+/calcineurin/NF-ATc signalling pathway is essential for normal cardiac valve and septum morphogenesis; hence, NF-ATc and its regulatory pathways are candidates for genetic defects underlying congenital human heart disease.

[1]  A. Cumano,et al.  Defects in cardiac outflow tract formation and pro-B-lymphocyte expansion in mice lacking Sox-4 , 1996, Nature.

[2]  Christoph W. Turck,et al.  Nuclear Export of NF-ATc Enhanced by Glycogen Synthase Kinase-3 , 1997, Science.

[3]  A. Rao,et al.  Nuclear factor of activated T cells contains Fos and Jun , 1992, Nature.

[4]  Raymond B. Runyan,et al.  Signal transduction of a tissue interaction during embryonic heart development. , 1990, Cell regulation.

[5]  T. Hoey,et al.  Isolation of two new members of the NF-AT gene family and functional characterization of the NF-AT proteins. , 1995, Immunity.

[6]  M. Buckingham,et al.  Transcripts of alpha-cardiac and alpha-skeletal actins are early markers for myogenesis in the mouse embryo. , 1988, Development.

[7]  G. Crabtree,et al.  Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation , 1992, Nature.

[8]  G. Crabtree,et al.  Nuclear localization of NF-ATc by a calcineurin-dependent, cyclosporin-sensitive intramolecular interaction. , 1997, Genes & development.

[9]  Stuart L. Schreiber,et al.  Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes , 1991, Cell.

[10]  Howard Y. Chang,et al.  Asymmetric retraction of growth cone filopodia following focal inactivation of calcineurin , 1995, Nature.

[11]  M. Kirby,et al.  Neural crest cells contribute to normal aorticopulmonary septation. , 1983, Science.

[12]  G. Crabtree,et al.  Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin A , 1991, Nature.

[13]  Daryl J. Thomas,et al.  NFATc3, a Lymphoid-specific NFATc Family Member That Is Calcium-regulated and Exhibits Distinct DNA Binding Specificity (*) , 1995, The Journal of Biological Chemistry.

[14]  Peter Goodfellow,et al.  A gene mapping to the sex-determining region of the mouse Y chromosome is a member of a novel family of embryonically expressed genes , 1990, Nature.

[15]  E. A. O'neill,et al.  FK-506- and CsA-sensitive activation of the interleukin-2 promoter by calcineurin , 1992, Nature.

[16]  C. Lobe,et al.  Transcripts of Grg4, a murine groucho-related gene, are detected in adjacent tissues to other murine neurogenic gene homologues during embryonic development , 1996, Mechanisms of Development.

[17]  A. Joyner,et al.  A mouse model of Greig cephalo–polysyndactyly syndrome: the extra–toesJ mutation contains an intragenic deletion of the Gli3 gene , 1993, Nature Genetics.

[18]  G. Crabtree,et al.  Identification of a putative regulator of early T cell activation genes. , 1988, Science.

[19]  K. Ng,et al.  Cyclosporin A, an inhibitor of calcineurin, impairs memory formation in day-old chicks , 1996, Brain Research.

[20]  R R Markwald,et al.  Molecular regulation of atrioventricular valvuloseptal morphogenesis. , 1995, Circulation research.

[21]  C. Mickanin,et al.  Cell adhesion receptors and early mammalian heart development: an overview. , 1993, Comptes rendus de l'Academie des sciences. Serie III, Sciences de la vie.

[22]  G. Nolan,et al.  NF-AT components define a family of transcription factors targeted in T-cell activation , 1994, Nature.

[23]  A. Trumpp,et al.  The chicken limb deformity gene encodes nuclear proteins expressed in specific cell types during morphogenesis. , 1992, Genes & development.