Modulation of Notch Signaling at Early Stages of Differentiation of Human Induced Pluripotent Stem Cells to Dopaminergic Neurons
Nataliia V. KatolikovaAleksandr KhudiakovDaria D. ShafranskayaAndrey D. PrjibelskiAlexey E. MasharskiyMikael S. MorА. С. ГоловкинAnastasia K. ZaytsevaIrina NeganovaEvgeniya V. EfimovaRaul R. GainetdinovAnna Malashicheva
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Elaboration of protocols for differentiation of human pluripotent stem cells to dopamine neurons is an important issue for development of cell replacement therapy for Parkinson's disease. A number of protocols have been already developed; however, their efficiency and specificity still can be improved. Investigating the role of signaling cascades, important for neurogenesis, can help to solve this problem and to provide a deeper understanding of their role in neuronal development. Notch signaling plays an essential role in development and maintenance of the central nervous system after birth. In our study, we analyzed the effect of Notch activation and inhibition at the early stages of differentiation of human induced pluripotent stem cells to dopaminergic neurons. We found that, during the first seven days of differentiation, the cells were not sensitive to the Notch inhibition. On the contrary, activation of Notch signaling during the same time period led to significant changes and was associated with an increase in expression of genes, specific for caudal parts of the brain, a decrease of expression of genes, specific for forebrain, as well as a decrease of expression of genes, important for the formation of axons and dendrites and microtubule stabilizing proteins.Keywords:
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During embryonic and adult neurogenesis, neural stem cells (NSCs) generate the correct number and types of neurons in a temporospatial fashion. Control of NSC activity and fate is crucial for brain formation and homeostasis. Neurogenesis in the embryonic and adult brain differ considerably, but Notch signaling and inhibitor of DNA-binding (ID) factors are pivotal in both. Notch and ID factors regulate NSC maintenance; however, it has been difficult to evaluate how these pathways potentially interact. Here, we combined mathematical modeling with analysis of single-cell transcriptomic data to elucidate unforeseen interactions between the Notch and ID factor pathways. During brain development, Notch signaling dominates and directly regulates Id4 expression, preventing other ID factors from inducing NSC quiescence. Conversely, during adult neurogenesis, Notch signaling and Id2/3 regulate neurogenesis in a complementary manner and ID factors can induce NSC maintenance and quiescence in the absence of Notch. Our analyses unveil key molecular interactions underlying NSC maintenance and mechanistic differences between embryonic and adult neurogenesis. Similar Notch and ID factor interactions may be crucial in other stem cell systems.
Cell fate determination
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Notch signaling plays crucial roles in fate determination and the differentiation of neural stem cells in embryonic and adult brains. It is now clear that the notch pathway is under more complex and dynamic regulation than previously thought. To understand the functional details of notch signaling more precisely, it is important to reveal when, where, and how notch signaling is dynamically communicated between cells, for which the visualization of notch signaling is essential. In this review, we introduce recent technical advances in the visualization of notch signaling during neural development and in the adult brain, and we discuss the physiological significance of dynamic regulation of notch signaling.
Hes3 signaling axis
Notch proteins
Cyclin-dependent kinase 8
Cell fate determination
Cell Signaling
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Hes3 signaling axis
Notch proteins
Cell Signaling
Cyclin-dependent kinase 8
Cell fate determination
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The evolutionarily conserved NOTCH signaling displays pleotropic functions in almost every organ system with a simple signaling axis. Different from many other signaling pathways that can be amplified via kinase cascades, NOTCH signaling does not contain any intermediate to amplify signal. Thus, NOTCH signaling can be activated at distinct signaling strength levels, disruption of which leads to various developmental disorders. Here, we reviewed mechanisms establishing different NOTCH signaling strengths, developmental processes sensitive to NOTCH signaling strength perturbation, and transcriptional regulations influenced by NOTCH signaling strength changes. We hope this could add a new layer of diversity to explain the pleotropic functions of NOTCH signaling pathway.
Hes3 signaling axis
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Notch proteins
Hes3 signaling axis
Cell fate determination
Cell Signaling
Cyclin-dependent kinase 8
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Hes3 signaling axis
Notch proteins
Cyclin-dependent kinase 8
Cell Signaling
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The Notch signaling pathway is known to govern various aspects of tissue differentiation during embryonic development by mediating local cell-cell interactions that often control cell fate. The conserved components that underlie Notch signaling have been isolated in vertebrates, leading to a biochemical delineation of a core Notch signaling pathway and functional studies of this pathway during embryogenesis. Herein we highlight recent progress in determining how Notch signaling contributes to the development of the vertebrate embryo. We first discuss the role of Notch in the process of segmentation where rapid changes have been shown to occur in both the spatial and temporal aspects of Notch signaling, which are critical for segmental patterning. Indeed, the role of Notch in segmentation re-emphasizes a recurring question in Notch biology: how are the components involved in Notch signaling regulated to ensure their dynamic properties? Second, we address this question by discussing recent work on the biochemical mechanisms that potentially regulate Notch signaling during segmentation, including those that act on the receptors, ligands, and signal transduction apparatus.
Somitogenesis
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Cell Signaling
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Hairless
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The Notch signaling pathway is important for cell fate decisions in embryonic development and adult life. Defining the functional importance of the Notch pathway in these contexts requires the elucidation of essential signal transduction components that have not been fully characterized. Here, we show that Rabconnectin-3B is required for the Notch pathway in mammalian cells. siRNA-mediated silencing of Rabconnectin-3B in mammalian cells attenuated Notch signaling and disrupted the activation and nuclear accumulation of the Notch target Hes1. Rabconnectin-3B knockdown also disrupted V-ATPase activity in mammalian cells, consistent with previous observations in Drosophila. Pharmacological inhibition of the V-ATPase complex significantly reduced Notch signaling in mammalian cells. Finally, Rabconnectin-3B knockdown phenocopied functional disruption of Notch signaling during osteoclast differentiation. Collectively, these findings define an important role for Rabconnectin-3 and V-ATPase activity in the Notch signaling pathway in mammalian cells.
Hes3 signaling axis
HES1
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Cyclin-dependent kinase 8
Cell Signaling
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