The nuclear factor-jB (NF-jB) signalling pathway serves a crucial role in regulating the transcriptional responses of physiological processes that include cell division, cell survival, differentiation, immunity and inflammation. Here we outline studies using mouse models in which the core components of the NF-jB pathway, namely the IjB kinase subunits (IKKa, IKKb and NEMO), the IjB proteins (IjBa, IjBb, IjBe and Bcl-3) and the five NF-jB transcription factors (NF-jB1, NF-jB2, c-Rel, RelA and RelB), have been genetically manipulated using transgenic and knockout technology.
During thymopoiesis, a unique program of gene expression promotes the development of CD4 regulatory T (T reg) cells. Although Foxp3 maintains a pattern of gene expression necessary for T reg cell function, other transcription factors are emerging as important determinants of T reg cell development. We show that the NF-κB transcription factor c-Rel is highly expressed in thymic T reg cells and that in c-rel−/− mice, thymic T reg cell numbers are markedly reduced as a result of a T cell–intrinsic defect that is manifest during thymocyte development. Although c-Rel is not essential for TGF-β conversion of peripheral CD4+CD25− T cells into CD4+Foxp3+ cells, it is required for optimal homeostatic expansion of peripheral T reg cells. Despite a lower number of peripheral T reg cells in c-rel−/− mice, the residual peripheral c-rel−/− T reg cells express normal levels of Foxp3, display a pattern of cell surface markers and gene expression similar to those of wild-type T reg cells, and effectively suppress effector T cell function in culture and in vivo. Collectively, our results indicate that c-Rel is important for both the thymic development and peripheral homeostatic proliferation of T reg cells.
Toll-like receptor (TLR) signaling leads to the activation of mitogen-activated protein kinase and nuclear factor-jB signaling pathways. While the upstream signaling events initiated at the level of adaptors and the activation of the downstream signaling pathways have received a lot of attention, our understanding of how these signaling pathways are coordinated to regulate gene expression is poorly understood. This review gives a selective overview on our current understanding of signaling downstream of TLRs, with an emphasis on how the upstream kinases like the mitogen-activated protein kinase kinase kinases (TAK1 and Tpl2) and inhibitor of j-B kinase (IKK) coordinate the signaling events that steer the course of an immune response. Keywords: TLR signaling; Tpl2; ERK; NF-kB; gene regulation Toll-like receptors (TLRs) comprise a family of conserved cell surface and intracellular proteins that serve as innate immune sensors of specific microbial components termed as pathogen-associated molecular patterns (PAMPs). 1 Through a series of adaptor proteins recruited to PAMP-activated TLRs, the engagement of a number of key downstream intracellular signaling pathways determines the specificity, intensity and duration of the specific patterns of gene expression that ultimately steer the course of the innate and subsequent adaptive immune responses. 2-6 Signals emanating from TLRs diverge at the level of mitogen-activated protein kinase kinase kinases (MAP3Ks), which act as activation nodes for nuclear factorkB (NF-kB) and the mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38. 7 The NF-kB family of transcription factors comprises homodimers and heterodimers of five related proteins [NF-kB1 (p105/p50), NFkB2 (p100/p52), c-Rel, RelA (p65) and RelB]. 8 In unstimulated cells, they are held as inactive complexes in the cytoplasm by inhibitor of kB (IkB) proteins. TLR signaling via the MAP3K, TAK1 leads to the activation of the inhibitor of kB kinase (IKK) complex, 7,9,10 comprising two catalytic (IKKa and IKKb) and a regulatory (NEMO) subunit. IkK-mediated phosphorylation of IkB targets it for ubiquitin-dependent proteasome-mediated degradation, thereby releasing NF-kB to be translocated to the nucleus where it regulates the transcription of genes encoding inflammatory and immune mediators through the recognition and binding decameric sequences (kB elements) found in the regulatory regions of target genes.The MAP kinase signaling pathways function as three-tiered kinase cascades resulting in the activation of the effector kinases, JNK, p38 and ERK. The initial step in TLR-induced MAPK activation involves two distinct MAP3Ks, TAK1 and Tpl2. While TAK1 activates JNK and p38 via the kinase intermediates (MAP2Ks), MKK3 and MKK6, 7 Tpl2 phosphorylation of the MAP2Ks, MEK1 and MEK2 result in ERK activation. [11][12][13] This review while mainly focusing on the mechanisms by which MAPK-and NF-kB-dependent gene expression is co-coordinated in response to TLR ...
Dopamine powerfully controls neural circuits through neuromodulation. In the vertebrate striatum, dopamine adjusts cellular functions to regulate behaviors across broad time scales, but how the dopamine secretory system is built to support fast and slow neuromodulation is not known. Here, we set out to identify Ca2+-triggering mechanisms for dopamine release. We find that synchronous dopamine secretion is abolished in acute brain slices of conditional knockout mice in which Synaptotagmin-1 is removed from dopamine neurons. This indicates that Synaptotagmin-1 is the Ca2+ sensor for fast dopamine release. Remarkably, dopamine release induced by strong depolarization and asynchronous release during stimulus trains are unaffected by Synaptotagmin-1 knockout. Microdialysis further reveals that these modes and action potential-independent release provide significant amounts of extracellular dopamine in vivo. We propose that the molecular machinery for dopamine secretion has evolved to support fast and slow signaling modes, with fast release requiring the Ca2+ sensor Synaptotagmin-1.
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