Cardiac T-box factor Tbx20 directly interacts with Nkx2-5, GATA4, and GATA5 in regulation of gene expression in the developing heart

Stennard, Fiona A.; Costa, Mauro W.; Elliott, David A.; Rankin, Scott A.; Haast, Saskia Jp; Lai, Donna; McDonald, Lachlan; Niederreither, Karen; Dollé, Pascal; Bruneau, Benoit G.; Zorn, Aaron M.; Harvey, Richard P.

doi:10.1016/s0012-1606(03)00385-3

Cited by 260 publications

(311 citation statements)

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“…In cardiomyocytes, the homeobox transcription factor Nkx2-5 regulates expression of Hopx [27,28]. Interestingly, the T-box transcription factors T-box 5 and 20 have been shown to form a functional complex with Nkx2-5 [62][63][64].…”

Section: Discussionmentioning

confidence: 99%

Persistence of effector memory Th1 cells is regulated by Hopx

et al. 2010

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Th1 cells are prominent in inflamed tissue, survive conventional immunosuppression, and are believed to play a pivotal role in driving chronic inflammation. Here, we identify homeobox only protein (Hopx) as a critical and selective regulator of the survival of Th1 effector/memory cells, both in vitro and in vivo. Expression of Hopx is induced by T-bet and increases upon repeated antigenic restimulation of Th1 cells. Accordingly, the expression of Hopx is low in peripheral, naïve Th cells, but highly up-regulated in terminally differentiated effector/memory Th1 cells of healthy human donors. In murine Th1 cells, Hopx regulates the expression of genes involved in regulation of apoptosis and survival and makes them refractory to Fas-induced apoptosis. In vivo, adoptively transferred Hopxdeficient murine Th1 cells do not persist. Consequently, they cannot induce chronic inflammation in murine models of transfer-induced colitis and arthritis, demonstrating a key role of Hopx for Th1-mediated immunopathology.Key words: Cell survival . CD4 T cells . Inflammation . Memory cells Supporting Information available onlineIntroduction T-helper type 1 (Th1) cells mediate immune responses to intracellular pathogens, such as viruses, and produce IFN-g as their signature cytokine [1]. IFN-g, together with IL-12 and the transcription factors STAT1, STAT4 and T-bet, promotes the development of Th1 cells [2][3]. T-bet (T-box 21) is considered to act as the master transcription factor critically regulating Th1 lineage commitment [3][4][5]. Apart from their protective role in clearing infections, Th1 cells can initiate and maintain chronic inflammatory diseases, e.g. inflammatory bowel disease [6][7][8][9], uveitis [10], EAE [11,12] and arthritis [13]. In vitro, Th1 cells are much more sensitive to Fas-mediated apoptosis than Th2 or Th17 cells [14][15][16][17][18][19][20]. In vivo, however, effector/memory Th1 cells are abundant in chronically inflamed tissue [21][22][23] and persist over long time periods [24][25][26], suggesting that their sensitivity to Eur. J. Immunol. 2010. 40: 2993-3006 DOI 10.1002 HIGHLIGHTS 2993 FrontlineFas-mediated apoptosis is strictly regulated. Here, we demonstrate that among CD4 1 T cells, the transcriptional cofactor homeobox only protein (Hopx) is expressed by repeatedly restimulated Th1 cells, but not by Th2, Th17 or regulatory T cells. Hopx regulates Fas-mediated apoptosis of effector/memory Th1 cells and is critically required for their persistence in vivo.In vertebrates, Hopx expression originally was detected in the myocardium [27,28]. There, expression of Hopx is induced by the cardiac transcription factor Nkx2-5. Hopx-deficient mice show a complex, incompletely penetrant phenotype. Some Hopxdeficient embryos have a poorly developed myocardium with reduced cell numbers, others show normal, and still others show increased numbers of cardiomyocytes after birth [27,28]. Hopx does not bind to homeobox consensus binding sequences, and it has been postulated that Hopx acts indirectly, partnering with ...

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Section: Discussionmentioning

confidence: 99%

Persistence of effector memory Th1 cells is regulated by Hopx

et al. 2010

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“…Because the binding sites for STAT3 and T are located in close proximity to one another in the Nanog EM enhancer and because both T box transcription factors (17)(18)(19) and STAT3 (20, 21) have been described as physically interacting with other transcription factors for the regulation of specific promoters, we decided to analyze whether T and STAT3 could interact inside the cell. We tested this possibility in NIH 3T3 cells by cotransfecting expression vectors encoding tagged versions of STAT3 and T (FLAG-STAT3 and Myc-T) and carrying out immunoprecipitation assays.…”

Section: T-and Stat-bindingmentioning

confidence: 99%

Nanog binds to Smad1 and blocks bone morphogenetic protein-induced differentiation of embryonic stem cells

Suzuki

Raya

Kawakami

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

240

182

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ES cells represent a valuable model for investigating early embryo development and hold promise for future regenerative medicine strategies. The self-renewal of pluripotent mouse ES cells has been shown to require extrinsic stimulation by the bone morphogenetic protein (BMP) and leukemia inhibitory factor signaling pathways and the expression of the transcription factors Oct4 and Nanog. However, the network of interactions among extrinsic and intrinsic determinants of ES cell pluripotency is currently poorly understood. Here, we show that Nanog expression is up-regulated in mouse ES cells by the binding of T (Brachyury) and STAT3 to an enhancer element in the mouse Nanog gene. We further show that Nanog blocks BMP-induced mesoderm differentiation of ES cells by physically interacting with Smad1 and interfering with the recruitment of coactivators to the active Smad transcriptional complexes. Taken together, our findings illustrate the existence of ES cellspecific regulatory networks that underlie the maintenance of ES cell pluripotency and provide mechanistic insights into the role of Nanog in this process.pluripotency ͉ T (Brachyury) ͉ self-renewal ͉ mesoderm differentiation ͉ leukemia inhibitory factor M ouse ES cells are self-renewing, pluripotent cell lines derived from preimplantation embryos (1, 2). Strict culture conditions must be followed to maintain the self-renewal of pluripotent mouse ES cells. Two extrinsic culture requirements, a feeder layer of fibroblasts and the addition of FBS, have been identified as necessary to sustain proliferation of undifferentiated mouse ES cells and their activities pinpointed to specific molecules (reviewed in ref. 3). Thus, self-renewal of mouse ES cells can be sustained in feeder-free conditions by supplementing the culture media with the cytokine leukemia inhibitory factor (LIF) (4, 5). In the absence of LIF, ES cell colonies flatten and form epithelium-like sheets (4, 5). More recently, the self-renewal promoting activity of animal serum has been identified as being mediated by ligands of specific families of the TGF-␤ superfamily, including the bone morphogenetic protein (BMP) family members BMP2 and BMP4 and the growth and differentiation factor (GDF) family member GDF6 (6). In the absence of BMP͞GDF signals, LIF is not sufficient to prevent the neural differentiation of ES cells, whereas the absence of both BMP͞GDF and LIF stimulation results in a flattened cell phenotype similar to that observed during LIF withdrawal (6).The intracellular signaling cascades initiated by both LIF and BMP͞GDF that sustain self-renewal of mouse ES cells have been worked out to a significant degree of detail (reviewed in ref.3). In summary, binding of LIF to its cognate LIF receptor results in the recruitment of gp130 and the formation of a ternary complex that catalyzes the tyrosine phosphorylation, dimerization, and nuclear translocation of the downstream signal transducer STAT3. BMP͞ GDF, in turn, promotes ES cell self-renewal by inducing the expression of members of the inhibit...

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“…The RNA-binding protein hermes also regulates Nkx2.5 expression (Gerber et al, 2002). Tbx5, Tbx20, myocardin, and islet1 are transcription factors that interact with Nkx2.5 and GATAs and regulate gene expression in the precardiac region (Stennard et al, 2003, Small et al, 2005, Brade et al, 2007. Both the Notch signal (Notch1, Serrate1, and Delta1) and hyaluronan matrix (Xhas2, Xversican, and XHAPLN3) genes are essential for the correct specification of myocardial cell fates (Rones et al, 2000.…”

Section: In Vitro Differentiation Of Pronephros and Molecular Analysimentioning

confidence: 99%

In vitro organogenesis from undifferentiated cells in Xenopus

Asashima

Ito

Chan

et al. 2009

Developmental Dynamics

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Amphibians have been used for over a century as experimental animals. In the field of developmental biology in particular, much knowledge has been accumulated from studies on amphibians, mainly because they are easy to observe and handle. Xenopus laevis is one of the most intensely investigated amphibians in developmental biology at the molecular level. Thus, Xenopus is highly suitable for studies on the mechanisms of organ differentiation from not only a single fertilized egg, as in normal development, but also from undifferentiated cells, as in the case of in vitro organogenesis. Based on the established in vitro organogenesis methods, we have identified many genes that are indispensable for normal development in various organs. These experimental systems are useful for investigations of embryonic development and for advancing regenerative medicine. Developmental Dynamics 238:1309 -1320, 2009.

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Cardiac T-box factor Tbx20 directly interacts with Nkx2-5, GATA4, and GATA5 in regulation of gene expression in the developing heart

Cited by 260 publications

References 100 publications

Persistence of effector memory Th1 cells is regulated by Hopx

Persistence of effector memory Th1 cells is regulated by Hopx

Nanog binds to Smad1 and blocks bone morphogenetic protein-induced differentiation of embryonic stem cells

In vitro organogenesis from undifferentiated cells in Xenopus

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