Cross-talk between the Notch and TGF-β signaling pathways mediated by interaction of the Notch intracellular domain with Smad3

Blokzijl, Andries; Dahlqvist, Camilla; Reissmann, Eva; Falk, Anna; Moliner, Annalena; Lendahl, Urban; Ibáñez, Carlos F.

doi:10.1083/jcb.200305112

Cited by 345 publications

(299 citation statements)

References 25 publications

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“…Although the conclusion above is the most likely, the data at hand could still support the notion that TGF-␤ signaling is enhancing Notch-mediated effector function, rather than the other way around. This arises from that fact that while in these studies we showed that Notch signaling enhances TGF-␤ function, in other studies cited above the enhancement was mutual (28). This latter possibility would be supported by evidence that Notch signaling has an inherently negative effect on T cell and/or APC function; however, this does not seem to be the case.…”

Section: Discussioncontrasting

confidence: 42%

“…Upon binding with its ligands (Jagged1 and 2 and Delta-like1, 3, and 4), it releases its intracellular domain into the cytoplasm which then translocates to the nucleus (19). Recently, it has been shown that the released signaling models arising from Notch1 activation enhance Smad signaling function in fibroblast and other mesenchymal cells (28), suggesting that Notch1 signaling could interact with the TGF-␤ signaling occurring in Treg function.…”

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confidence: 99%

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Notch1 Signaling and Regulatory T Cell Function

Asano

Watanabe

Kitani

et al. 2008

The Journal of Immunology

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Previous studies have shown that the Notch1 and TGF-β signaling pathways are mutually re-enforcing. Given recent evidence that regulatory T cell (Treg) effector function is mediated by TGF-β signaling, we investigated whether Notch1 signaling also participated in Treg effector function. Initial studies showed that Notch1 ligands, particularly Jagged1, are present on Tregs and that, indeed, blockade of Notch1 signaling with an anti-Jagged1 or a blocking anti-Notch1 Ab inhibits Treg suppressor function in vitro. We then showed that a signaling component generated by Notch1 activation (Notch1 intracellular domain) of dendritic cells physically interacts with a signaling component generated by TGF-β signaling (pSmad3). Furthermore, this interaction has functional downstream effects because over-expression of Notch1 intracellular domain facilitates pSmad3 translocation to the nucleus and enhances pSmad3 transcriptional activity of a Smad-sensitive promoter linked to a luciferase reporter. Finally, we showed that blockade of TGF-β signaling and Notch signaling did not have additive inhibitory effects on Treg suppressor function. These results are consistent with the conclusion that Notch1 signaling facilitates TGF-β-mediated effector function of Tregs.

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Section: Discussioncontrasting

confidence: 42%

mentioning

confidence: 99%

Notch1 Signaling and Regulatory T Cell Function

Asano

Watanabe

Kitani

et al. 2008

The Journal of Immunology

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“…Moreover, previous results have shown an interaction between Notch and TGF-β pathways [8][9][10]. We surmise that Notch1 affects effector T-cell responses in the presence of Treg cells through a TGF-β signaling mechanism.…”

Section: Notch Suppresses the Proliferation Of Cd4 + Cd25 − T Cells Tsupporting

confidence: 60%

Notch activation on effector T cells increases their sensitivity to Treg cell‐mediated suppression through upregulation of TGF‐βRII expression

et al. 2012

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Notch proteins play an important role in embryonic development and cell-fate decisions. Notch influences also the activation and differentiation of peripheral T cells. Here, we investigated whether Notch signaling modulates the response of effector T cells to regulatory T (Treg) cells. Pre-exposure of CD4 + CD25 − effector T cells to the Notch ligandsDelta-4 and Jagged-1, but not Delta-1, increases significantly effector T-cell sensitivity to Treg cell-mediated suppression through upregulation of TGF-βRII expression and increased levels of the phosphorylated form of the Smad 3 protein. This effect is relieved by anti-TGF-β Abs. We demonstrate that HES (hairy and enhancer of split), the main transcription factor downstream of Notch, induces strong transactivation of TGF-ßRII by binding the TGF-βRII promoter through its DNA-binding domain. Thus, the crosstalk between Notch and the TGF-β pathway leads to potentiation of the suppressive effect of Treg cells. Keywords:Immune regulation r Notch signaling r Regulatory T cells r TGF-βRII IntroductionThe Notch signaling system is conserved from Drosophila to humans and regulates cell differentiation, proliferation, and survival. Notch pathways play an important role in embryonic development, T-cell development and function, and in disease processes, including carcinogenesis and autoimmunity. In mammals there are four Notch receptors (1-4) and five Notch ligands (Jagged-1, Jagged-2, Delta-like 1 (DL-1), [1].Notch proteins exert their pleiotropic effects through the regulation of expression of various downstream genes, many of which require the interaction of Notch proteins with the DNA binding transcription factor CSL (also known as CBF1, Su(H), Correspondence: Prof. Yves Levy e-mail: yves.levy@hmn.aphp.fr and LAG-1) in order to form a short-lived nuclear transcription complex [2]. After engagement with its ligands, successive proteolytic events cause clipping of the Notch protein. The first is mediated by ADAM proteases and the second by the γ-secretase complex, in which presenilins (PS1 and PS2) constitute the active center of the enzyme complex. These proteolytic events ultimately release the intracellular domain of Notch (NICD). The formation of a complex of activated intracellular Notch protein and CSL converts CSL from a transcriptional repressor to a transcriptional transactivator. The genes encoding the HES (hairy and enhancer of split) family of basic helix-loop-helix proteins are Notch targets that are known to be essential for T-cell development and signaling. * These authors have contributed equally to this work.www.eji-journal.eu Eur. J. Immunol. 2012. 42: 1796-1803 Immunomodulation 1797In addition to influencing , Notch signaling has also been involved in the differentiation and expansion of regulatory T (Treg) cells [4]. Several reports have shown that the presence of Notch ligands, mostly of the Jagged family, can enhance Treg-cell differentiation and function in vitro [5]. For example, exposure of Treg cells to Jagged-2 expressed by hematopoietic progen...

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“…It is well established that Hes1 expression can be regulated by Notch/Rbpjκ-independent signaling before E8.5 (Hatakeyama et al, 2004;Kageyama et al, 2005). Additionally, Rbpjκ-independent expression of Notch factors, including Hes genes, can be mediated by members of the BMP (Dahlqvist et al, 2003;Itoh et al, 2004) Kadesch, 2001), WNT/β-catenin (Axelrod et al, 1996;Hayward et al, 2005) and Shh (Wall et al, 2009) pathways throughout embryonic development. However, only a few studies have shown that Hes5 can be modulated by Notch/Rbpjκ-independent signaling occurring at two distinct time points: before E8.5 (Donoviel et al, 1999;Hitoshi et al, 2011) and during adult neurogenesis (Matsuda et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Notch/Rbpjκ signaling regulates progenitor maintenance and differentiation of hypothalamic arcuate neurons

Aujla

Naratadam

et al. 2013

Development

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SUMMARYThe hypothalamic arcuate nucleus (Arc), containing pro-opoiomelanocortin (POMC), neuropeptide Y (NPY) and growth hormone releasing hormone (GHRH) neurons, regulates feeding, energy balance and body size. Dysregulation of this homeostatic mediator underlies diseases ranging from growth failure to obesity. Despite considerable investigation regarding the function of Arc neurons, mechanisms governing their development remain unclear. Notch signaling factors such as Hes1 and Mash1 are present in hypothalamic progenitors that give rise to Arc neurons. However, how Notch signaling controls these progenitor populations is unknown. To elucidate the role of Notch signaling in Arc development, we analyzed conditional loss-of-function mice lacking a necessary Notch co-factor, Rbpjκ, in Nkx2.1-cre-expressing cells (Rbpjκ cKO), as well as mice with expression of the constitutively active Notch1 intracellular domain (NICD) in Nkx2.1-cre-expressing cells (NICD Tg). We found that loss of Rbpjκ results in absence of Hes1 but not of Hes5 within the primordial Arc at E13.5. Additionally, Mash1 expression is increased, coincident with increased proliferation and accumulation of Arc neurons at E13.5. At E18.5, Rbpjκ cKO mice have few progenitors and show increased numbers of differentiated Pomc, NPY and Ghrh neurons. By contrast, NICD Tg mice have increased hypothalamic progenitors, show an absence of differentiated Arc neurons and aberrant glial differentiation at E18.5. Subsequently, both Rbpjκ cKO and NICD Tg mice have changes in growth and body size during postnatal development. Taken together, our results demonstrate that Notch/Rbpjκ signaling regulates the generation and differentiation of Arc neurons, which contribute to homeostatic regulation of body size. KEY WORDS: Arcuate, Notch, POMC, NPY, Hypothalamus, MouseNotch/Rbpjκ signaling regulates progenitor maintenance and differentiation of hypothalamic arcuate neurons Paven K. Aujla, George T. Naratadam, Liwen Xu and Lori T. Raetzman* DEVELOPMENT 3512During embryonic development, cells migrate from the hypothalamic ventricular zone (HVZ) surrounding the ventral region of the third ventricle in order to form the Arc by E16.5 (Bayer and Altman, 1987;Ishii and Bouret, 2012;Shimada and Nakamura, 1973). One of the major functions of the Arc is to respond to food intake and energy expenditure. Energy-related hormone signals such as leptin are sensed by anorexic proopoiomelanocortin (POMC)/cocaine and amphetamine-regulated transcript (CART) neurons and orexic neuropeptide Y (NPY)/Agouti-related peptide (AgRP) neurons. POMC and NPY neurons regulate feeding behavior and are crucial to maintaining proper energy balance and homeostasis (Broberger, 2005;Morton et al., 2006;Srinivas et al., 2001). An additional subtype of neurons, growth hormone-releasing hormone (GHRH) neurons, are present in the Arc and regulate body size and growth by controlling release of growth hormone from the pituitary gland (Bouyer et al., 2007; Grossman et al., 1986).Despite the functional importance of ...

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Cross-talk between the Notch and TGF-β signaling pathways mediated by interaction of the Notch intracellular domain with Smad3

Cited by 345 publications

References 25 publications

Notch1 Signaling and Regulatory T Cell Function

Notch1 Signaling and Regulatory T Cell Function

Notch activation on effector T cells increases their sensitivity to Treg cell‐mediated suppression through upregulation of TGF‐βRII expression

Notch/Rbpjκ signaling regulates progenitor maintenance and differentiation of hypothalamic arcuate neurons

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