Notch signaling regulates the FOXP3 promoter through RBP-J- and Hes1-dependent mechanisms

Ou‐Yang, Hai‐Feng; Zhang, Hongwei; Wu, Changgui; Zhang, Ping; Zhang, Jian; Li, Junchang; Hou, Lihong; He, Fangping; Ti, Xinyu; Song, Liqiang; Zhang, Suzhen; Feng, Lei; Qi, Hao-wen; Han, Hua

doi:10.1007/s11010-008-9912-4

Cited by 45 publications

(40 citation statements)

References 23 publications

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“…8). In this sense, our previous study also demonstrates that Rbpj and Hes1 can simultaneously regulate Foxp3 transcription in a bi-phasic manner (Ou-Yang et al, 2009). Our in vitro and in vivo gene expression assays provided the functional evidence that Rbpj per se is capable of promoting Ascl1 expression, though it also repressed Ascl1 expression indirectly in the presence of Hes1 (Fig.…”

Section: Lc Hyperplasia In Rbpj Cko Mice Is Due To Enhanced Ascl1 Expsupporting

confidence: 72%

Notch-Rbpj signaling is required for the development of noradrenergic neurons in mouse locus coeruleus

Shi

Zheng

et al. 2012

Journal of Cell Science

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SummaryThe locus coeruleus (LC) is the main source of noradrenaline in the brain and is implicated in a broad spectrum of physiological and behavioral processes. However, genetic pathways controlling the development of noradrenergic neurons in the mammalian brain are largely unknown. We report here that Rbpj, a key nuclear effector in the Notch signaling pathway, plays an essential role in LC neuron development in the mouse. Conditional inactivation of Rbpj in the dorsal rhombomere (r) 1, where LC neurons are born, resulted in a dramatic increase in the number of Phox2a-and Phox2b-expressing early-differentiating LC neurons, and dopamine-b-hydroxylase-and tyrosine-hydroxylase-expressing late-differentiating LC neurons. In contrast, other neuronal populations derived from the dorsal r1 were either reduced or unchanged. In addition, a drastic upregulation of Ascl1, an essential factor for noradrenergic neurogenesis, was observed in dorsal r1 of conditional knockout mice. Through genomic sequence analysis and EMSA and ChIP assays, a conserved Rbpjbinding motif was identified within the Ascl1 promoter. A luciferase reporter assay revealed that Rbpj per se could induce Ascl1 transactivation but this effect was counteracted by its downstream-targeted gene Hes1. Moreover, our in vitro gene transfection and in ovo electroporation assays showed that Rbpj upregulated Ascl1 expression when Hes1 expression was knocked down, although it also exerted a repressive effect on Ascl1 expression in the presence of Hes1. Thus, our results provide the first evidence that Rbpj functions as a key modulator of LC neuron development by regulating Ascl1 expression directly, and indirectly through its target gene Hes1.

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Section: Lc Hyperplasia In Rbpj Cko Mice Is Due To Enhanced Ascl1 Expsupporting

confidence: 72%

Notch-Rbpj signaling is required for the development of noradrenergic neurons in mouse locus coeruleus

Shi

Zheng

et al. 2012

Journal of Cell Science

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“…105 Other pathways which are involved in the direct regulation of the Foxp3 gene include the aryl hydrocarbon receptor, which can induce Foxp3 expression in Treg cells by binding to the conserved aryl hydrocarbon receptor-binding sites in the Foxp3 promoter. 106 The notch pathway has also been implicated in negatively controlling Foxp3 expression 107 through Hes1, which can interact with the promoter region of the Foxp3 gene 108 and also by signaling through the protein kinase C and canonical NF-kB pathways. 109 Finally, Bcl11b has also been shown to increase the suppressive nature of Treg cells, and was found to regulate the genes that encode Foxp3 and IL-10.…”

Section: Il-2 and Its Receptor Il-2r Are Crucial For The Expansion Anmentioning

confidence: 99%

Molecular mechanisms underlying the regulation and functional plasticity of FOXP3+ regulatory T cells

et al. 2011

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CD4þ CD25 þ regulatory T (Treg) cells engage in the maintenance of immunological self-tolerance and homeostasis by limiting aberrant or excessive inflammation. The transcription factor forkhead box P3 (FOXP3) is critical for the development and function of Treg cells. The differentiation of the Treg cell lineage is not terminal, as developmental and functional plasticity occur through the sensing of inflammatory signals in the periphery. Here, we review the recent progress in our understanding of the molecular mechanisms underlying the regulation and functional plasticity of CD4 þ CD25 þ FOXP3 þ Treg cells, through the perturbation of FOXP3 and its complex at a transcriptional, translational and post-translational level.

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“…Interestingly, it has also been documented that the transcription factor forkhead box O3a (FoxO3a) is a key negative transcriptional target of canonical Notch1 signaling, exerting a protective function in the UVBinduced apoptosis in skin keratinocytes (Mandinova et al, 2008). Similarly, N1-ICD regulates the transcription factor forkhead box P3 (FOXP3) promoter through RBP-J-and Hes-1-dependent mechanisms in FOXP3 + CD4 + CD25 + regulatory T cells, or 'Tregs' (Ou-Yang et al, 2009;Radtke et al, 2010). These data suggest that FOX-related genes might be a common downstream target of the canonical Notch signaling in different cell types.…”

Section: Discussionmentioning

confidence: 99%

Notch gain of function in mouse periocular mesenchyme downregulates FoxL2 and impairs eyelid levator muscle formation, leading to congenital blepharophimosis

Zhang

Kao

Pelosi

et al. 2011

Journal of Cell Science

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SummaryNotch signaling is pivotal for the morphogenesis and homeostasis of many tissues. We found that aberrant Notch activation in mouse neural-crest-derived periocular mesenchymal cells (POMCs), which contribute to the formation of corneal and eyelid stroma, results in blepharophimosis. Compound transgenic mice overexpressing the Notch1 intracellular domain (N1-ICD) in POMCs (POMC N1-ICD ) showed relatively minor effects on the cornea, but increased cell apoptosis and decreased cell proliferation during eyelid morphogenesis. Eyelid closure at E15.5 and eyelid formation at birth were incomplete. In further analyses, overexpression of N1-ICD impaired eyelid levator smooth muscle formation by downregulating the transcription factor FoxL2. This is similar to the effect of haploinsufficiency of FOXL2 in humans, which results in type II BPES (blepharophimosis, ptosis and epicanthus inversus syndrome). In vitro studies showed that FoxL2 expression is augmented by a low dose of N1-ICD but was downregulated by a high dose, depending on the extent of Hes-1 and Hey-1 activation. Moreover, transfection of CMV-FoxL2 enhanced -SMA promoter activity. These data strongly imply that a physiologically low level of Notch1 is crucial for proper FoxL2 expression in POMCs, which is, in turn, essential for Müeller muscle formation and normal eyelid development.

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Notch signaling regulates the FOXP3 promoter through RBP-J- and Hes1-dependent mechanisms

Cited by 45 publications

References 23 publications

Notch-Rbpj signaling is required for the development of noradrenergic neurons in mouse locus coeruleus

Notch-Rbpj signaling is required for the development of noradrenergic neurons in mouse locus coeruleus

Molecular mechanisms underlying the regulation and functional plasticity of FOXP3+ regulatory T cells

Notch gain of function in mouse periocular mesenchyme downregulates FoxL2 and impairs eyelid levator muscle formation, leading to congenital blepharophimosis

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