The adult mammalian heart has limited potential for regeneration. Thus, after injury, cardiomyocytes are permanently lost, and contractility is diminished. In contrast, the neonatal heart can regenerate owing to sustained cardiomyocyte proliferation. Identification of critical regulators of cardiomyocyte proliferation and quiescence represents an important step toward potential regenerative therapies. Yes-associated protein (Yap), a transcriptional cofactor in the Hippo signaling pathway, promotes proliferation of embryonic cardiomyocytes by activating the insulin-like growth factor and Wnt signaling pathways. Here we report that mice bearing mutant alleles of Yap and its paralog WW domain containing transcription regulator 1 ( Taz ) exhibit gene dosage-dependent cardiac phenotypes, suggesting redundant roles of these Hippo pathway effectors in establishing proper myocyte number and maintaining cardiac function. Cardiac-specific deletion of Yap impedes neonatal heart regeneration, resulting in a default fibrotic response. Conversely, forced expression of a constitutively active form of Yap in the adult heart stimulates cardiac regeneration and improves contractility after myocardial infarction. The regenerative activity of Yap is correlated with its activation of embryonic and proliferative gene programs in cardiomyocytes. These findings identify Yap as an important regulator of cardiac regeneration and provide an experimental entry point to enhance this process.

H. Multiple renal cysts, urinary concentration defects, and pulmonary emphysematous changes in mice lacking TAZ.

The T-box transcription factor TBX5 plays essential roles in cardiac and limb development. Various mutations in the TBX5 gene have been identified in patients with Holt-Oram syndrome, which is characterized by congenital defects in the heart and upper extremities. In this study, we identified a WW-domain-containing transcriptional regulator TAZ as a potent TBX5 coactivator. TAZ directly associates with TBX5 and markedly stimulates TBX5-dependent promoters by interacting with the histone acetyltransferases p300 and PCAF. YAP, a TAZ-related protein with conserved functional domains, also stimulates TBX5-dependent transcription, possibly by forming a heterodimer with TAZ. TBX5 lacks a PY motif, which mediates the association of other proteins with TAZ, and interacts with TAZ through multiple domains including its carboxyl-terminal structure. Truncation mutants of TBX5 identified in patients with Holt-Oram syndrome were markedly impaired in their ability to associate with and be stimulated by TAZ. These findings reveal key roles for TAZ and YAP in the control of TBX5-dependent transcription and suggest the involvement of these coactivators in cardiac and limb development.transcriptional coactivator ͉ organ development ͉ hereditary birth defects T he activation of specific programs of gene expression during cell differentiation and organ development depends on combinatorial interactions among DNA-binding transcription factors, transcriptional cofactors, and histone-modifying enzymes (1, 2). Additional specificity and fine-tuning of gene expression is achieved by signal-dependent modulation of the expression and activity of the components of such multiprotein transcriptional complexes.Members of the T-box family of transcription factors regulate a variety of developmental processes in vertebrates and invertebrates, including specification of mesoderm, development of the heart, vasculature, and limbs and tumorigenesis (3-5). The T-box, which encodes a conserved 180-amino acid DNA-binding domain, has been identified in at least 18 mammalian T-box genes. In many cases, haploinsufficiency of T-box genes results in dramatic morphological abnormalities, emphasizing the importance of specific thresholds of transcriptional activity of T-box factors for developmental decisions (4). For example, heterozygous mutations in TBX1 have been implicated in 22q11 deletion (DiGeorge) syndrome, characterized by abnormalities in the aortic arch arteries due to defects in neural crest cell migration (4, 6), and mutations in TBX5 cause Holt-Oram syndrome (HOS), which manifests as a variety of cardiac and upper limb abnormalities (7-11).TBX5 is expressed in the embryonic heart and forelimbs and regulates transcription of downstream genes, such as those encoding atrial natriuretic factor (ANF) and fibroblast growth factor 10 (Fgf10) by binding to TBX-binding DNA elements (TBEs) (12-17). Targeted deletion of the Tbx5 gene in mice results in embryonic lethality with severe cardiac defects (13), and mice with limb-specific Tbx5 deletion show no ...

Studies on transgenic mice expressing immunoglobulins against self-antigens have shown that self-tolerance is maintained by active elimination (clonal deletion), functional inactivation (clonal anergy) of self-reactive B cells, or a combination of both. We have established and characterized a transgenic mouse line expressing an anti-erythrocyte autoantibody. In contrast to other autoantibody transgenic lines, about 50% of the animals of this transgenic line suffer from autoimmune disease, indicating a loss of self-tolerance. Here we show that peritoneal Ly-1 B cells (also known as B-1 cells) are responsible for this autoimmune disease in our transgenic mice. A few self-reactive Ly-1 B cells that have somehow escaped the deletion mechanism expand in the peritoneum because of the absence of self-antigen. These Ly-1 B cells are eliminated in vivo by apoptosis once exposed to self-antigen. On the basis of these results we propose a novel autoantibody production mechanism whereby self-reactive B cells sequestered in compartments free of self-antigens may survive, proliferate and be activated for generation of pathogenic autoantibodies in autoimmune diseases.

SummaryWe made double transgenic mice bearing immunoglobulin heavy and light chain genes encoding an autoantibody against the mouse erythrocyte by the cross of C57BL/6 mice carrying the transgene for each chain of the immunoglobulin. Although no obvious disorders were found in the singlechain transgenic mice, severely anemic symptoms were found in some of the double transgenic mice, in which most B cells express, at least on their surface, the autoantibody reactive to selfantigens on the erythrocyte. Individual double-transgenic mice showed a wide variation of phenotypes between severe anemia and no symptoms. Both deletion and anergy of autoreactive B cells were seen in each individual mouse, but their relative contribution to self-tolerance was variable and not directly related to the severity of anemia or the amount of the autoantibody produced. This transgenic system provides a good autoimmune disease model for exploring its onset mechanism, and means of its treatment and prevention.