The imprinted gene Delta like non-canonical Notch ligand 1 (Dlk1) is conserved in mammals, and serves a growth modulatory role during tissue development and regeneration through Notch dependent and independent mechanisms

Traustadóttir, Gunnhildur Ásta; Lagoni, Lene Vig; Ankerstjerne, Lea Bo Sønderlund; Bisgaard, Hanne Cathrine; Jensen, Charlotte Harken; Andersen, Ditte Caroline

doi:10.1016/j.cytogfr.2019.03.006

Cited by 49 publications

(40 citation statements)

References 148 publications

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“…The inhibitory role of DLK1 and DLK2 proteins on NOTCH activation and signaling [8,[17][18][19][20][21][22]35] has been confirmed in many works of the scientific community [4,17,22,23,32,35,37,[96][97][98][99][100][101][102]. Recently, we observed that both DLK proteins inhibit each of the four NOTCH receptors' activities [18,19].…”

Section: Discussionmentioning

confidence: 71%

“…Recently, we observed that both DLK proteins inhibit each of the four NOTCH receptors' activities [18,19]. However, some authors have also reported that the DLK1 protein does not affect NOTCH signaling [37,[103][104][105][106], or even that it activates NOTCH signaling [25,91,[107][108][109]. Together with the existence of different DLK1 protein and probably DLK2 protein isoforms, self-and cross-interactions previously reported [22,110,111] could explain some of the contradictory effects reported for DLK proteins on NOTCH activation and signaling.…”

Section: Discussionmentioning

confidence: 86%

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NOTCH Receptors and DLK Proteins Enhance Brown Adipogenesis in Mesenchymal C3H10T1/2 Cells

Rodríguez-Cano

González-Gómez

Sánchez-Solana

et al. 2020

Cells

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The NOTCH family of receptors and ligands is involved in numerous cell differentiation processes, including adipogenesis. We recently showed that overexpression of each of the four NOTCH receptors in 3T3-L1 preadipocytes enhances adipogenesis and modulates the acquisition of the mature adipocyte phenotype. We also revealed that DLK proteins modulate the adipogenesis of 3T3-L1 preadipocytes and mesenchymal C3H10T1/2 cells in an opposite way, despite their function as non-canonical inhibitory ligands of NOTCH receptors. In this work, we used multipotent C3H10T1/2 cells as an adipogenic model. We used standard adipogenic procedures and analyzed different parameters by using quantitative-polymerase chain reaction (qPCR), quantitative reverse transcription-polymerase chain reaction (qRT-PCR), luciferase, Western blot, and metabolic assays. We revealed that C3H10T1/2 multipotent cells show higher levels of NOTCH receptors expression and activity and lower Dlk gene expression levels than 3T3-L1 preadipocytes. We found that the overexpression of NOTCH receptors enhanced C3H10T1/2 adipogenesis levels, and the overexpression of NOTCH receptors and DLK (DELTA-like homolog) proteins modulated the conversion of cells towards a brown-like adipocyte phenotype. These and our prior results with 3T3-L1 preadipocytes strengthen the idea that, depending on the cellular context, a precise and highly regulated level of global NOTCH signaling is necessary to allow adipogenesis and determine the mature adipocyte phenotype.

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 86%

NOTCH Receptors and DLK Proteins Enhance Brown Adipogenesis in Mesenchymal C3H10T1/2 Cells

Rodríguez-Cano

González-Gómez

Sánchez-Solana

et al. 2020

Cells

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“…In this study, we observed cell type and time-specific expression of Dlk1 during muscle regeneration processes. Because Dlk1 expression is detected in proliferative hepatoblasts from the fetal liver [21,22] and in cancer cells [23,24], Dlk1 expression may also reflect the proliferative ability of mesenchymal progenitors. However, we observed that suppression of Dlk1 in mesenchymal progenitors did not affect the process of muscle regeneration.…”

Section: Discussionmentioning

confidence: 99%

Expression and Functional Analyses of Dlk1 in Muscle Stem Cells and Mesenchymal Progenitors during Muscle Regeneration

Zhang

Uezumi

Kaji

et al. 2019

IJMS

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Delta like non-canonical Notch ligand 1 (Dlk1) is a paternally expressed gene which is also known as preadipocyte factor 1 (Pref−1). The accumulation of adipocytes and expression of Dlk1 in regenerating muscle suggests a correlation between fat accumulation and Dlk1 expression in the muscle. Additionally, mice overexpressing Dlk1 show increased muscle weight, while Dlk1-null mice exhibit decreased body weight and muscle mass, indicating that Dlk1 is a critical factor in regulating skeletal muscle mass during development. The muscle regeneration process shares some features with muscle development. However, the role of Dlk1 in regeneration processes remains controversial. Here, we show that mesenchymal progenitors also known as adipocyte progenitors exclusively express Dlk1 during muscle regeneration. Eliminating developmental effects, we used conditional depletion models to examine the specific roles of Dlk1 in muscle stem cells or mesenchymal progenitors. Unexpectedly, deletion of Dlk1 in neither the muscle stem cells nor the mesenchymal progenitors affected the regenerative ability of skeletal muscle. In addition, fat accumulation was not increased by the loss of Dlk1. Collectively, Dlk1 plays essential roles in muscle development, but does not greatly impact regeneration processes and adipogenic differentiation in adult skeletal muscle regeneration.

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“…While many functions of DLK1 appear related to its potential regulation of Notch signaling [10], other studies have found no evidence of Notch dependency for DLK1 [11], suggesting that the role of DLK1 can vary. Signaling from DLK1 can involve ADAM17-mediated release of its extracellular domain [12,13], with best-described consequences in inhibition of adipocyte differentiation. Mechanisms involve activation of the MEK/ERK pathway and Sox9 [14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-induced release, nuclear translocation, and signaling activity of a DLK1 intracellular fragment in glioma

2020

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Glioblastoma multiforme is characterized in part by severe hypoxia associated with tumor necrosis. The cellular response to hypoxia can influence several properties of tumor cells associated with aggressive tumor growth, including metabolic adaptations and tumor cell migration and invasion. Here, we found that Delta Like Non-Canonical Notch Ligand 1 (DLK1) expression was elevated as compared with normal brain in a genetically engineered mouse model of glioma, and that DLK1 expression increased with tumor grade in human glioma samples. DLK1 expression was highest in hypoxic and perivascular tumor areas, and we found that hypoxia induced the release and nuclear translocation of an intracellular fragment of DLK1 in murine glioma as well as in human glioma cultures. Release of the intracellular fragment was dependent on ADAM17 and Hypoxia-inducible Factor 1alpha and 2alpha (HIF-1alpha/HIF-2alpha), as ADAM17 inhibitors and HIF1A/HIF2A siRNA blocked DLK1 cleavage. Expression of a cleavable form of DLK1 amplified several hypoxia-induced traits of glioma cells such as colony formation, stem cell marker gene expression, a PI3K-pathway-mediated metabolic shift, and enhanced invasiveness. Effects of DLK1 were dependent on DLK1-cleavage by ADAM17, as expression of non-cleavable DLK1 could not replicate the DLK1-induced hypoxic phenotype. Finally, forced expression of DLK1 resulted in more invasive tumor growth in a PDGFB-induced glioma mouse model without affecting overall survival. Together, our findings suggest a previously undescribed role for DLK1 as an intracellular signaling molecule.

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The imprinted gene Delta like non-canonical Notch ligand 1 (Dlk1) is conserved in mammals, and serves a growth modulatory role during tissue development and regeneration through Notch dependent and independent mechanisms

Abstract: The imprinted gene Delta like non-canonical Notch ligand 1 (Dlk1) is conserved in mammals, and serves a growth modulatory role during tissue development and regeneration through Notch dependent and independent mechanisms

Cited by 49 publications

References 148 publications

NOTCH Receptors and DLK Proteins Enhance Brown Adipogenesis in Mesenchymal C3H10T1/2 Cells

NOTCH Receptors and DLK Proteins Enhance Brown Adipogenesis in Mesenchymal C3H10T1/2 Cells

Expression and Functional Analyses of Dlk1 in Muscle Stem Cells and Mesenchymal Progenitors during Muscle Regeneration

Hypoxia-induced release, nuclear translocation, and signaling activity of a DLK1 intracellular fragment in glioma

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