Role of the Non-Canonical Notch Ligand Delta-Like Protein 1 in Hormone-Producing Cells of the Adult Male Mouse Pituitary

Puertas-Avendaño, Ricardo; González-Gómez, María-Julia; Ruvira, María Desamparados; Ruiz-Hidalgo, Marı́a José; Morales-Delgado, Nicanor; Laborda, Jorge; Dı́az, Carmen; Bello, Aixa R.

doi:10.1111/j.1365-2826.2011.02189.x

Cited by 26 publications

(50 citation statements)

References 45 publications

(59 reference statements)

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“…e observed expression pattern of DLK1 in the developing pituitary implies that DLK1 is also involved in regulating the differentiation of pituitary cell types, probably by modulating Notch signalling activity. In agreement, adult pituitary of Dlk1 knockout mice showed decreased numbers of growthhormone immunoreactive cells and reduced follicle stimulating hormone (FSH) and prolactin immunoreactivity [36].…”

Section: Dlk1 and Notch During Pituitary Gland Developmentsupporting

confidence: 51%

DLK1 Protein Expression during Mouse Development Provides New Insights into Its Function

Falix

Tjon-A-Loi

Gaemers

et al. 2013

ISRN Developmental Biology

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Delta-like 1 homolog (DLK1) is a noncanonical ligand in the Delta-Notch signalling pathway. Although Dlk1 mRNA is abundantly present embryonically and declines rapidly just before birth, Dlk1 knockouts display a relatively mild phenotype. To assess whether this mild phenotype was due to posttranscriptional regulation, we studied the expression of DLK1 protein in mouse embryos and found abundant expression in liver, lung, muscle, vertebrae, pancreas, pituitary, and adrenal gland(s). DLK1 expression was absent in heart, stomach, intestine, kidney, epidermis, and central nervous system. DLK1 protein expression, therefore, correlates well with the reported Dlk1 mRNA expression pattern, which shows that its expression is mainly regulated at the pretranslational level. The comparison of the reported expression patterns of Notch mRNA and those of DLK1 in organs where lineage commitment and branching morphogenesis are important developmental processes suggests that DLK1 is a ligand that prevents premature Notch-dependent differentiation, possibly by competing with canonical ligands.

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Section: Dlk1 and Notch During Pituitary Gland Developmentsupporting

confidence: 51%

DLK1 Protein Expression during Mouse Development Provides New Insights into Its Function

Falix

Tjon-A-Loi

Gaemers

et al. 2013

ISRN Developmental Biology

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“…Several previous studies have implicated DLK1 in GH regulation (38)(39)(40)(41), and also conversely GH in the regulation of DLK1 (42)(43)(44). Notably, a recent study reported a reduction in GH secretion after Dlk1 deletion (40).…”

Section: Discussionmentioning

confidence: 96%

DLK1/PREF1 regulates nutrient metabolism and protects from steatosis

Charalambous

Rocha

Radford

et al. 2014

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

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Significance Hepatosteatosis or nonalcoholic fatty liver disease (NAFLD) is an important health problem affecting approximately 20% of the population of the United States and is associated with cardiovascular risk factors such as insulin resistance and obesity. Using a Delta-like homologue (Dlk1) [also known as preadipocyte factor 1 (Pref1)] transgenic model, we identified a new player in the growth hormone (GH) signaling pathway that, when overexpressed, is protective against obesity and hepatosteatosis. Because the dosage of circulating DLK1 is naturally elevated in early life and during pregnancy, we believe that our transgenic model mimics endogenous mechanisms of DLK1-mediated GH signaling modulation that are used during periods of metabolic stress to protect from steatosis and alter fuel utilization in the whole organism.

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“…Mouse macrophages express Dlk1 moderately as compared with other cell types [32][33][34]. However, human monocytes, and the human monocytic cell line U937, express higher levels of DLK1 that diminish after their differentiation to macrophages, whereas, in general, the expression of NOTCH receptors increases in this process.…”

Section: Discussionmentioning

confidence: 99%

“…In this sense, our previous work revealed that Dlk1-deficient mice showed an increased primary T-dependent antibody response [31]. These results are consistent with an improved antigen presentation by macrophages and dendritic cells from Dlk1-null animals, which can be due, at least in part, to a greater expression of co-stimulatory molecules and cytokines implicated in T-cell differentiation.Mouse macrophages express Dlk1 moderately as compared with other cell types [32][33][34]. However, human monocytes, and the human monocytic cell line U937, express higher levels of DLK1 that diminish after their differentiation to macrophages, whereas, in general, the expression of NOTCH receptors increases in this process.…”

mentioning

confidence: 99%

DLK1 is a novel inflammatory inhibitor which interferes with NOTCH1 signaling in TLR‐activated murine macrophages

González¹,

Ruiz-García²,

Monsalve³

et al. 2015

Eur J Immunol

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Delta-like protein 1 (DLK1) is a noncanonical ligand that inhibits NOTCH1 receptor activity and regulates multiple differentiation processes. In macrophages, NOTCH signaling increases TLR-induced expression of key pro-inflammatory mediators. We have investigated the role of DLK1 in macrophage activation and inflammation using Dlk1-deficient mice and Raw 264.7 cells overexpressing Dlk1. In the absence of Dlk1, NOTCH1 expression is increased and the activation of macrophages with TLR3 or TLR4 agonists leads to higher production of IFN-β and other pro-inflammatory cytokines, including TNF-α, IL-12, and IL-23. The expression of key proteins involved in IFN-β signaling, such as IRF3, IRF7, IRF1, or STAT1, as well as cRel, or RelB, which are responsible for the generation of IL-12 and IL-23, is enhanced in Dlk1 KO macrophages. Consistently, Dlk1 KO mice are more sensitive to LPS-induced endotoxic shock. These effects seem to be mediated through the modulation of NOTCH1 signaling. TLR4 activation reduces DLK1 expression, whereas increases NOTCH1 levels. In addition, DLK1 expression diminishes during differentiation of human U937 cells to macrophages. Overall, these results reveal a novel role for DLK1 as a regulator of NOTCH-mediated, pro-inflammatory macrophage activation, which could help to ensure a baseline level preventing constant tissue inflammation.Keywords: Cytokine r DLK1 r Inflammatory inhibitor r Macrophage r NOTCH signaling r TLR Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMacrophages are key cells in innate and adaptive immune response to pathogens. Toll-like receptors (TLR) recognize conserved microbial structures and induce the activation of macrophages, thus increasing their phagocytic and cytotoxic activities, and leading to the production of inflammatory cytokines, Correspondence: Dr. María J. Ruiz-Hidalgo and Dr. María J. M. Díaz-Guerra e-mail: Maria.RHidalgo@uclm.es; MariaJose.Martinez@uclm.es such as TNF-α and IL-1, and cytokines of the IL-6 and IL-12 families, which regulate T-cell differentiation [1].Macrophages display a remarkable plasticity and can change their functioning in response to environmental signals, which allows a fine-tuning of their activity to adapt to different situations. Unrestrained activation of TLR responses can lead to excessive inflammation and tissue damage and contribute to the pathogenesis of inflammatory disorders, such as septic shock. Multiple mechanisms are implicated in the control of macrophage activation, including inhibitory cytokines, transcriptional repressors, and epigenetic modifications [2,3].C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 2616 María J. González et al. Eur. J. Immunol. 2015. 45: 2615-2627 In this line, a critical role for NOTCH signaling in macrophage activation and polarization has been evidenced [4][5][6]. Ligand binding to the NOTCH receptors triggers a two-step proteolytic cleavage causing the release of the NOTCH intracellular doma...

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Role of the Non-Canonical Notch Ligand Delta-Like Protein 1 in Hormone-Producing Cells of the Adult Male Mouse Pituitary

Cited by 26 publications

References 45 publications

DLK1 Protein Expression during Mouse Development Provides New Insights into Its Function

DLK1 Protein Expression during Mouse Development Provides New Insights into Its Function

DLK1/PREF1 regulates nutrient metabolism and protects from steatosis

DLK1 is a novel inflammatory inhibitor which interferes with NOTCH1 signaling in TLR‐activated murine macrophages

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