scholarly journals Anabolic actions of Notch on mature bone

2016 ◽  
Vol 113 (15) ◽  
pp. E2152-E2161 ◽  
Author(s):  
Peng Liu ◽  
Yilin Ping ◽  
Meng Ma ◽  
Demao Zhang ◽  
Connie Liu ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Bone Matrix ◽  
Reporter Mice ◽  
Egfp Reporter ◽  
Adult Bone ◽  
Bone Remains ◽  
Notch Activation ◽  
Time Point ◽  
Stimulation Of ◽  
Mature Bone

Notch controls skeletogenesis, but its role in the remodeling of adult bone remains conflicting. In mature mice, the skeleton can become osteopenic or osteosclerotic depending on the time point at which Notch is activated or inactivated. Using adult EGFP reporter mice, we find that Notch expression is localized to osteocytes embedded within bone matrix. Conditional activation of Notch signaling in osteocytes triggers profound bone formation, mainly due to increased mineralization, which rescues both age-associated and ovariectomy-induced bone loss and promotes bone healing following osteotomy. In parallel, mice rendered haploinsufficient in γ-secretase presenilin-1 (Psen1), which inhibits downstream Notch activation, display almost-absent terminal osteoblast differentiation. Consistent with this finding, pharmacologic or genetic disruption of Notch or its ligand Jagged1 inhibits mineralization. We suggest that stimulation of Notch signaling in osteocytes initiates a profound, therapeutically relevant, anabolic response.

scholarly journals Mind bomb 1 in the lymphopoietic niches is essential for T and marginal zone B cell development

2008 ◽  
Vol 205 (11) ◽  
pp. 2525-2536 ◽  
Author(s):  
Ran Song ◽  
Young-Woong Kim ◽  
Bon-Kyoung Koo ◽  
Hyun-Woo Jeong ◽  
Mi-Jeong Yoon ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Marginal Zone ◽  
T Cell Development ◽  
Cell Development ◽  
Lymphocyte Development ◽  
E3 Ligases ◽  
Reporter Mice ◽  
Transplantation Experiments ◽  
Notch Ligands ◽  
Notch Activation

Notch signaling regulates lineage decisions at multiple stages of lymphocyte development, and Notch activation requires the endocytosis of Notch ligands in the signal-sending cells. Four E3 ubiquitin ligases, Mind bomb (Mib) 1, Mib2, Neuralized (Neur) 1, and Neur2, regulate the Notch ligands to activate Notch signaling, but their roles in lymphocyte development have not been defined. We show that Mib1 regulates T and marginal zone B (MZB) cell development in the lymphopoietic niches. Inactivation of the Mib1 gene, but not the other E3 ligases, Mib2, Neur1, and Neur2, abrogated T and MZB cell development. Reciprocal bone marrow (BM) transplantation experiments revealed that Mib1 in the thymic and splenic niches is essential for T and MZB cell development. Interestingly, when BM cells from transgenic Notch reporter mice were transplanted into Mib1-null mice, the Notch signaling was abolished in the double-negative thymocytes. In addition, the endocytosis of Dll1 was impaired in the Mib1-null microenvironment. Moreover, the block in T cell development and the failure of Dll1 endocytosis were also observed in coculture system by Mib1 knockdown. Our study reveals that Mib1 is the essential E3 ligase in T and MZB cell development, through the regulation of Notch ligands in the thymic and splenic microenvironments.

scholarly journals Current Views on the Roles of O-Glycosylation in Controlling Notch-Ligand Interactions

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 309
Author(s):  
Wataru Saiki ◽  
Chenyu Ma ◽  
Tetsuya Okajima ◽  
Hideyuki Takeuchi
Keyword(s):  
Notch Signaling ◽  
100Th Anniversary ◽  
Notch Receptor ◽  
Notch Receptors ◽  
Evolutionarily Conserved ◽  
Future Challenges ◽  
Ligand Interactions ◽  
Epidermal Growth ◽  
Notch Activation ◽  
Human Specific

The 100th anniversary of Notch discovery in Drosophila has recently passed. The Notch is evolutionarily conserved from Drosophila to humans. The discovery of human-specific Notch genes has led to a better understanding of Notch signaling in development and diseases and will continue to stimulate further research in the future. Notch receptors are responsible for cell-to-cell signaling. They are activated by cell-surface ligands located on adjacent cells. Notch activation plays an important role in determining the fate of cells, and dysregulation of Notch signaling results in numerous human diseases. Notch receptors are primarily activated by ligand binding. Many studies in various fields including genetics, developmental biology, biochemistry, and structural biology conducted over the past two decades have revealed that the activation of the Notch receptor is regulated by unique glycan modifications. Such modifications include O-fucose, O-glucose, and O-N-acetylglucosamine (GlcNAc) on epidermal growth factor-like (EGF) repeats located consecutively in the extracellular domain of Notch receptors. Being fine-tuned by glycans is an important property of Notch receptors. In this review article, we summarize the latest findings on the regulation of Notch activation by glycosylation and discuss future challenges.

Cell proliferation control by Notch signaling in Drosophila development

Development ◽  
1998 ◽  
Vol 125 (11) ◽  
pp. 2031-2040 ◽  
Author(s):  
M.J. Go ◽  
D.S. Eastman ◽  
S. Artavanis-Tsakonas
Keyword(s):  
Cell Proliferation ◽  
Notch Signaling ◽  
Imaginal Disc ◽  
Synergistic Effects ◽  
Wing Disc ◽  
Notch Receptor ◽  
Simple Consequence ◽  
Undifferentiated Cells ◽  
Cell Proliferation Control ◽  
Stimulation Of

The Notch receptor mediates cell interactions controlling the developmental fate of a broad spectrum of undifferentiated cells. By modulating Notch signaling in specific precursor cells during Drosophila imaginal disc development, we demonstrate that Notch activity can influence cell proliferation. The activation of the Notch receptor in the wing disc induces the expression of the wing margin patterning genes vestigial and wingless, and strong mitotic activity. However, the effect of Notch signaling on cell proliferation is not the simple consequence of the upregulation of either vestigial or wingless. Vestigial and Wingless, on the contrary, display synergistic effects with Notch signaling, resulting in the stimulation of cell proliferation in imaginal discs.

Renal tubular Notch signaling triggers a prosenescent state after acute kidney injury

2014 ◽  
Vol 306 (8) ◽  
pp. F907-F915 ◽  
Author(s):  
Inga Sörensen-Zender ◽  
Song Rong ◽  
Nathan Susnik ◽  
Steffen Zender ◽  
Petra Pennekamp ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Ischemia Reperfusion ◽  
Butyl Ester ◽  
Kidney Injury ◽  
Acute Injury ◽  
Tubular Damage ◽  
Tubular Atrophy ◽  
Aging Kidney ◽  
Notch Activation

The aging kidney has a diminished regenerative potential and an increased tendency to develop tubular atrophy and fibrosis after acute injury. In this study, we found that activation of tubular epithelial Notch1 signaling was prolonged in the aging kidney after ischemia/reperfusion (IR) damage. To analyze the consequences of sustained Notch activation, we generated mice with conditional inducible expression of Notch1 intracellular domain (NICD) in proximal tubules. NICD kidneys were analyzed 1 and 4 wk after renal IR. Conditional NICD expression was associated with aggravated tubular damage, a fibrotic phenotype, and the expression of cellular senescence markers p21 and p16 INK4a. In wild-type mice pharmacological inhibition of Notch using the γ-secretase inhibitor N-[ N-(3,5-difluorophenacetyl)-l-alanyl]- S-phenylglycine t-butyl ester (DAPT) improved tubulo-interstitial damage and antagonized the prosenescent pathway activation after IR. In vitro, activation of Notch signaling with delta-like-ligand-4 caused prosenescent changes in tubular cells while inhibition with DAPT attenuated these changes. In conclusion, our data suggest that sustained epithelial Notch activation after IR might contribute to the inferior outcome of old kidneys after injury. Sustained epithelial activation of Notch is associated with a prosenescent phenotype and maladaptive repair.

Abstract A9: Pharmacological stimulation of DLL1-Notch signaling as an antitumor immunotherapy

2012 ◽  
Vol 18 (3 Supplement) ◽  
pp. A9-A9
Author(s):  
Yuhui Huang ◽  
Luping Lin ◽  
Asel K. Biktasova ◽  
Anshu Malhotra ◽  
Anil Shanker ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Pharmacological Stimulation ◽  
Antitumor Immunotherapy ◽  
Stimulation Of

scholarly journals Age-Dependent Activation and Neuronal Differentiation of Lgr5+ Basal Cells in Injured Olfactory Epithelium via Notch Signaling Pathway

2020 ◽  
Vol 12 ◽  
Author(s):  
Xuewen Li ◽  
Meimei Tong ◽  
Li Wang ◽  
Yumei Qin ◽  
Hongmeng Yu ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Signaling Pathway ◽  
Sensory Neurons ◽  
Olfactory Epithelium ◽  
Three Dimensional ◽  
Notch Signaling Pathway ◽  
Basal Cells ◽  
Aged Mice ◽  
Age Dependent ◽  
Notch Activation

Aging is an important factor affecting function of smell, leading to the degeneration of mature olfactory sensory neurons and inducing the occurrence of smell loss. The mammalian olfactory epithelium (OE) can regenerate when subjected to chemical assaults. However, this capacity is not limitless. Inactivation of globose basal cells and failure to generate sensory neurons are the main obstacles to prevent the OE regeneration. Here, we found the significant attenuation in mature sensory neuronal generation and apparent transcriptional alternation in the OE from aged mice compared with young ones. The recruitment of leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5)-positive cells in injured OE was weakened in aged mice, and more Lgr5+ cells remained quiescence in aged OE postinjury. Lineage-traced progenies from Lgr5+ cells were significantly fewer in the OE with aging. Moreover, Notch activation enhanced the neuronal regeneration in aged OE, making the regenerative capacity of aged OE comparable with that of young animals after injury. The growth and morphology of three-dimensional (3D)-cultured organoids from the OE of young and aged mice varied and was modulated by small molecules regulating the Notch signaling pathway. Thus, we concluded that activation of Lgr5+ cells in injured OE was age dependent and Notch activation could enhance the capacity of neuronal generation from Lgr5+ cells in aged OE after injury.

scholarly journals Epsins Regulate Mouse Embryonic Stem Cell Exit from Pluripotency and Neural Commitment by Controlling Notch Activation

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Marina Cardano ◽  
Jacopo Zasso ◽  
Luca Ruggiero ◽  
Giuseppina Di Giacomo ◽  
Matteo Marcatili ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Embryonic Stem Cells ◽  
Notch Signaling ◽  
Neural Differentiation ◽  
Radial Glia ◽  
Embryonic Stem ◽  
Mouse Embryonic Stem Cell ◽  
Neural Progenitors ◽  
Notch Activation

Epsins are part of the internalization machinery pivotal to control clathrin-mediated endocytosis. Here, we report that epsin family members are expressed in mouse embryonic stem cells (mESCs) and that epsin1/2 knockdown alters both mESC exits from pluripotency and their differentiation. Furthermore, we show that epsin1/2 knockdown compromises the correct polarization and division of mESC-derived neural progenitors and their conversion into expandable radial glia-like neural stem cells. Finally, we provide evidence that Notch signaling is impaired following epsin1/2 knockdown and that experimental restoration of Notch signaling rescues the epsin-mediated phenotypes. We conclude that epsins contribute to control mESC exit from pluripotency and allow their neural differentiation by appropriate modulation of Notch signaling.

scholarly journals Osteocytes mediate the anabolic actions of canonical Wnt/β-catenin signaling in bone

2015 ◽  
Vol 112 (5) ◽  
pp. E478-E486 ◽  
Author(s):  
Xiaolin Tu ◽  
Jesus Delgado-Calle ◽  
Keith W. Condon ◽  
Marta Maycas ◽  
Huajia Zhang ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Notch Signaling ◽  
Bone Matrix ◽  
Notch Pathway ◽  
Target Cells ◽  
Appendicular Skeleton ◽  
Mineral Density ◽  
Bone Formation Rate ◽  
Central Target ◽  
Canonical Wnt

Osteocytes, >90% of the cells in bone, lie embedded within the mineralized matrix and coordinate osteoclast and osteoblast activity on bone surfaces by mechanisms still unclear. Bone anabolic stimuli activate Wnt signaling, and human mutations of components along this pathway underscore its crucial role in bone accrual and maintenance. However, the cell responsible for orchestrating Wnt anabolic actions has remained elusive. We show herein that activation of canonical Wnt signaling exclusively in osteocytes [dominant active (da)βcatOt mice] induces bone anabolism and triggers Notch signaling without affecting survival. These features contrast with those of mice expressing the same daß-catenin in osteoblasts, which exhibit decreased resorption and perinatal death from leukemia. daßcatOt mice exhibit increased bone mineral density in the axial and appendicular skeleton, and marked increase in bone volume in cancellous/trabecular and cortical compartments compared with littermate controls. daßcatOt mice display increased resorption and formation markers, high number of osteoclasts and osteoblasts in cancellous and cortical bone, increased bone matrix production, and markedly elevated periosteal bone formation rate. Wnt and Notch signaling target genes, osteoblast and osteocyte markers, and proosteoclastogenic and antiosteoclastogenic cytokines are elevated in bones of daßcatOt mice. Further, the increase in RANKL depends on Sost/sclerostin. Thus, activation of osteocytic β-catenin signaling increases both osteoclasts and osteoblasts, leading to bone gain, and is sufficient to activate the Notch pathway. These findings demonstrate disparate outcomes of β-catenin activation in osteocytes versus osteoblasts and identify osteocytes as central target cells of the anabolic actions of canonical Wnt/β-catenin signaling in bone.

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