Biological Significance of NOTCH Signaling Strength

Shen, Wei; Huang, Jiaxin; Wang, Yan

doi:10.3389/fcell.2021.652273

Cited by 49 publications

(39 citation statements)

References 75 publications

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“…Our results, show a novel Notch dose-sensitivity for habenula asymmetry development, which may be a potential neural basis for the absence of biased behavior following low levels of Notch inhibition. Since Notch signaling is essential for diverse cellular functions, and the precise downstream signaling mechanisms are highly sensitive to the strength of Notch signaling ( De Smedt et al, 2005 ; Shen et al, 2021 ), the low inhibitor concentrations used may be sub-threshold for disturbing the spatial-temporal patterns of her12 and HuC/D tested here. In addition, the downstream effects of Notch are dependent on the cellular micro-environments, determined by the local co-expression of Notch receptors, ligands, and auxiliary proteins ( Demehri et al, 2009 ; Bertrand et al, 2011 ; LaFoya et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Environmental and Molecular Modulation of Motor Individuality in Larval Zebrafish

Hageter

Waalkes

Starkey

et al. 2021

Front. Behav. Neurosci.

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Innate behavioral biases such as human handedness are a ubiquitous form of inter-individual variation that are not strictly hardwired into the genome and are influenced by diverse internal and external cues. Yet, genetic and environmental factors modulating behavioral variation remain poorly understood, especially in vertebrates. To identify genetic and environmental factors that influence behavioral variation, we take advantage of larval zebrafish light-search behavior. During light-search, individuals preferentially turn in leftward or rightward loops, in which directional bias is sustained and non-heritable. Our previous work has shown that bias is maintained by a habenula-rostral PT circuit and genes associated with Notch signaling. Here we use a medium-throughput recording strategy and unbiased analysis to show that significant individual to individual variation exists in wildtype larval zebrafish turning preference. We classify stable left, right, and unbiased turning types, with most individuals exhibiting a directional preference. We show unbiased behavior is not due to a loss of photo-responsiveness but reduced persistence in same-direction turning. Raising larvae at elevated temperature selectively reduces the leftward turning type and impacts rostral PT neurons, specifically. Exposure to conspecifics, variable salinity, environmental enrichment, and physical disturbance does not significantly impact inter-individual turning bias. Pharmacological manipulation of Notch signaling disrupts habenula development and turn bias individuality in a dose dependent manner, establishing a direct role of Notch signaling. Last, a mutant allele of a known Notch pathway affecter gene, gsx2, disrupts turn bias individuality, implicating that brain regions independent of the previously established habenula-rostral PT likely contribute to inter-individual variation. These results establish that larval zebrafish is a powerful vertebrate model for inter-individual variation with established neural targets showing sensitivity to specific environmental and gene signaling disruptions. Our results provide new insight into how variation is generated in the vertebrate nervous system.

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Section: Discussionmentioning

confidence: 99%

Environmental and Molecular Modulation of Motor Individuality in Larval Zebrafish

Hageter

Waalkes

Starkey

et al. 2021

Front. Behav. Neurosci.

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“…Despite the established role of Notch in neural proliferation, we found no significant change in proliferative neurons or her12 expression at the dosages used for behavioral studies. Since Notch signaling is essential for diverse cellular functions, and the precise Notch mediated signaling mechanisms are highly sensitive to the strength of Notch signaling (De Smedt et al, 2005;Shen et al, 2021), the low inhibitor concentrations used may be sub-threshold for disturbing the spatial-temporal patterns of her12 and HuC/D tested here. In addition, the downstream effects of Notch are dependent on the cellular microenvironments, such as the co-expression of Notch receptors, ligands, and auxiliary proteins (Demehri et al, 2009;Bertrand et al, 2011;LaFoya et al, 2016).…”

Section: Regulation Of Individualitymentioning

confidence: 99%

Environmental and molecular modulation of motor individuality in larval zebrafish

Hageter

Waalkes

Starkey

et al. 2021

Preprint

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Innate behavioral biases such as human handedness are a ubiquitous form of inter-individual variation that are not strictly hardwired into the genome and are influenced by diverse internal and external cues. Yet, genetic and environmental factors modulating behavioral variation remain poorly understood, especially in vertebrates. To identify genetic and environmental factors that influence behavioral variation, we take advantage of larval zebrafish light-search behavior. During light-search, individuals preferentially turn in leftward or rightward loops, in which directional bias is sustained and non-heritable, and maintained by a habenula-rostral PT circuit. Here we use a medium-throughput recording strategy and unbiased analysis to show that significant individual to individual variation exists in wildtype larval zebrafish turning preference. We classify stable left, right, and unbiased turning types, with most individuals exhibiting a directional preference. Raising larvae at elevated temperature selectively reduces the leftward turning type and impacts rostral PT neurons, specifically. Exposure to conspecifics, variable salinity, environmental enrichment, and physical disturbance does not significantly impact inter-individual turning bias. Pharmacological manipulation of Notch signaling and carrying a mutant allele of a known Notch pathway affecter gene, gsx2, disrupted turn bias individuality in a dose-dependent manner. These results establish that larval zebrafish is a powerful vertebrate model for inter-individual variation with sensitivity to specific environmental perturbations and gene dosage.

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“…This signaling pathway involves direct intercellular interactions mediated by membrane-bound Notch ligands (Dll-1, Dll-4, Jag-1, Jag-2, and Dll-3) and Notch receptors (Notch 1 to 4). Following binding, Notch receptors are cleaved by A Disintegrin And Metalloproteinase domain-containing protein 10 (ADAM10) and γ-secretase releasing the notch intracellular domain (NICD) that translocates to the nucleus to act as a transcription factor (for review, see [130]). Notch stimulates the differentiation of Sca-1 + /CD146 − progenitor cells into pericytes [131], of Tie1 + precursors in SMC [132], of PDGFRβ + progenitor cells into SMC [133] and of MSC into SMC [85,134].…”

Section: Notchmentioning

confidence: 99%

Progenitor/Stem Cells in Vascular Remodeling during Pulmonary Arterial Hypertension

Dierick

Solinc

Bignard

et al. 2021

Cells

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Pulmonary arterial hypertension (PAH) is characterized by an important occlusive vascular remodeling with the production of new endothelial cells, smooth muscle cells, myofibroblasts, and fibroblasts. Identifying the cellular processes leading to vascular proliferation and dysfunction is a major goal in order to decipher the mechanisms leading to PAH development. In addition to in situ proliferation of vascular cells, studies from the past 20 years have unveiled the role of circulating and resident vascular in pulmonary vascular remodeling. This review aims at summarizing the current knowledge on the different progenitor and stem cells that have been shown to participate in pulmonary vascular lesions and on the pathways regulating their recruitment during PAH. Finally, this review also addresses the therapeutic potential of circulating endothelial progenitor cells and mesenchymal stem cells.

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Biological Significance of NOTCH Signaling Strength

Cited by 49 publications

References 75 publications

Environmental and Molecular Modulation of Motor Individuality in Larval Zebrafish

Environmental and Molecular Modulation of Motor Individuality in Larval Zebrafish

Environmental and molecular modulation of motor individuality in larval zebrafish

Progenitor/Stem Cells in Vascular Remodeling during Pulmonary Arterial Hypertension

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