The Notch signalling pathway and miRNA regulation play important roles in the differentiation of Schwann cells from adipose-derived stem cells

Abstract Objective: The proliferation and differentiation of developing neural stem cells (NSCs) have been particularly interesting targets to study ketamine-induced neurotoxicity. Our previous findings have shown that neonatal ketamine exposure inhibits the proliferation of NSCs in the hippocampal dentate gyrus (DG) and promotes neuronal differentiation. However, the potential mechanisms are poorly understood. Notch signalling pathway plays an important role in the regulation of neurogenesis. The objective of this study was to investigate whether Notch signalling pathway was involved in neurogenesis impairment and long-term neurocognitive dysfunction caused by neonatal ketamine exposure. Methods: Postnatal day 7 (PND-7) male Sprague-Dawley (SD) rats were intraperitoneally injected with normal saline (NS) or 40 mg/kg ketamine for four consecutive times (40 mg/kg×4) at an interval of 1 h. Notch ligand Jagged1 (0.5 mg/kg) was micro-injected into the hippocampal DG with the stereotactic apparatus at 1 h before NS or ketamine administration. Lentivirus over-expressing Notch1 intracellular domain (LV-NICD1) was micro-injected into the hippocampal DG 4 days before NS or ketamine administration. Western blot was used to detect the changes of Notch1 signalling pathway related proteins in the hippocampal DG at 24 h after administration. The S-phase marker 5-bromodeoxyuridine (BrdU) was administered immediately after the treatment, then the proliferation and differentiation of NSCs in hippocampal DG were detected by using double-immunofluorescence staining at 24 h after treatment. Moreover, the changes of hippocampus-dependent spatial memory in the adult rats were tested by Morris water maze test in 2-month-old rats. Results: Ketamine anesthesia in neonatal rats decreased the expression levels of Jagged1, Notch1, Notch1 intracellular domain (NICD1) and hairy enhancer of split 1 (Hes1), and inhibited the proliferation and astrocytic differentiation of NSCs and promoted neuronal differentiation. Neonatal ketamine exposure induced the deficit in hippocampus-dependent spatial reference memory tasks in 2-month-old rats. The micro-injection of Jagged1 or LV-NICD1 reversed the inhibitory effect of ketamine on the expression of Notch1 related proteins in the hippocampal DG, and attenuated the ketamine-induced interference of NSCs proliferation and differentiation. In addition, Morris water maze test suggested that the administration of Jagged1 or LV-NICD1 could improve cognitive function in 2-month-old rats after neonatal ketamine exposure. Conclusions: These results suggest that neonatal exposure to ketamine in rats interferes with the proliferation and differentiation of hippocampal NSCs and impairs neurocognitive function in adulthood via inhibition of Notch1 signalling pathway. These findings contribute to further understanding of the neonatal neurotoxicity induced by ketamine and its underlying mechanisms.

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The role of Notch ligand, Delta-like ligand 4 (DLL4), in cancer angiogenesis—implications for therapy

European Surgery ◽

10.1007/s10353-021-00707-x ◽

2021 ◽

Author(s):

Marlena Brzozowa-Zasada

Keyword(s):

Cancer Therapy ◽

Notch Signalling ◽

Signalling Pathway ◽

Gamma Secretase ◽

Tumour Angiogenesis ◽

Notch Signalling Pathway ◽

Expression Levels ◽

Blocking Agents ◽

Anti Cancer

Summary Background It is generally accepted that angiogenesis is a complex and tightly regulated process characterized by the growth of blood vessels from existing vasculature. Activation of the Notch signalling pathway affects multiple aspects of vascular development. One of the components of the Notch signalling pathway, Delta-like ligand 4 (DLL4), has recently appeared as a critical regulator of tumour angiogenesis and thus as a promising therapeutic target. Methods This review article includes available data from peer-reviewed publications associated with the role of DLL4 in cancer angiogenesis. Searches were performed in PubMed, EMBASE, Google Scholar and Web of Science using the terms “tumour angiogenesis”, “DLL4”, “Notch signalling” and “anti-cancer therapy”. Results The survival curves of cancer patients revealed that the patients with high DLL4 expression levels had significantly shorter survival times than the patients with low DLL4 expression. Moreover, a positive correlation was also identified between DLL4 and VEGF receptorsʼ expression levels. It seems that inhibition of DLL4 may exert potent growth inhibitory effects on some tumours resistant to anti-VEGF therapies. A great number of blocking agents of DLL4/Notch signalling including anti-DLL4 antibodies, DNA vaccination, Notch antibodies and gamma-secretase inhibitors have been studied in preclinical tumour models. Conclusion DLL4 seems to be a promising target in anti-cancer therapy. Nevertheless, the careful evaluation of adverse effects on normal physiological processes in relation to therapeutic doses of anti-DLL4 drugs will be significant for advancement of DLL4 blocking agents in clinical oncology.

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Zebrafish notch signalling pathway mutants exhibit trunk vessel patterning anomalies that are secondary to somite misregulation

Developmental Dynamics ◽

10.1002/dvdy.22410 ◽

2010 ◽

Vol 239 (10) ◽

pp. 2761-2768 ◽

Cited By ~ 10

Author(s):

Christina Therapontos ◽

Neil Vargesson

Keyword(s):

Notch Signalling ◽

Signalling Pathway ◽

Notch Signalling Pathway

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Novel players in the Notch signalling pathway

Developmental Biology ◽

10.1016/j.ydbio.2007.03.082 ◽

2007 ◽

Vol 306 (1) ◽

pp. 301

Author(s):

Hugo J. Bellen ◽

Melih Acar ◽

Hamed Jafar Nejad ◽

Anchi Tien ◽

Akhila Rajan

Keyword(s):

Notch Signalling ◽

Signalling Pathway ◽

Notch Signalling Pathway

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Conservation of the Notch signalling pathway in mammalian neurogenesis

Development ◽

10.1242/dev.124.6.1139 ◽

1997 ◽

Vol 124 (6) ◽

pp. 1139-1148 ◽

Cited By ~ 31

Author(s):

J.L. Pompa de la ◽

A. Wakeham ◽

K.M. Correia ◽

E. Samper ◽

S. Brown ◽

...

Keyword(s):

Cell Fate ◽

Notch Pathway ◽

Stem Cell Differentiation ◽

Notch Signalling ◽

Signalling Pathway ◽

Notch Signalling Pathway ◽

Altered Expression ◽

Cell Fate Decisions ◽

Targeted Mutation ◽

Multiple Cell

The Notch pathway functions in multiple cell fate determination processes in invertebrate embryos, including the decision between the neuroblast and epidermoblast lineages in Drosophila. In the mouse, targeted mutation of the Notch pathway genes Notch1 and RBP-Jk has demonstrated a role for these genes in somite segmentation, but a function in neurogenesis and in cell fate decisions has not been shown. Here we show that these mutations lead to altered expression of the Notch signalling pathway homologues Hes-5, Mash-1 and Dll1, resulting in enhanced neurogenesis. Precocious neuronal differentiation is indicated by the expanded expression domains of Math4A, neuroD and NSCL-1. The RBP-Jk mutation has stronger effects on expression of these genes than does the Notch1 mutation, consistent with functional redundancy of Notch genes in neurogenesis. Our results demonstrate conservation of the Notch pathway and its regulatory mechanisms from fly to mouse, and support a role for the murine Notch signalling pathway in the regulation of neural stem cell differentiation.

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