Second-generation Notch1 activity-trap mouse line (N1IP::CreHI) provides a more comprehensive map of cells experiencing Notch1 activity

Liu, Zhenyi; Brunskill, Eric W.; Boyle, Scott; Chen, Shuang; Turkoz, Mustafa; Guo, Yuxuan; Grant, Rachel; Kopan, Raphael

doi:10.1242/dev.119529

Cited by 20 publications

(23 citation statements)

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“…During postnatal development and along the spermatogenic cycle of adult male mouse, three Notch receptors (Notch 1-3) and ligands (Delta-like 1, 4 and Jagged 1, 2) were identified in the testis (Mori et al, 2003;Garcia & Hofmann, 2013;Murta et al, 2013;Okada et al, 2017;Kami nska et al, 2018). Although Notch receptors were identified both in germ and in Sertoli cells, Notch 1 signaling in adult seminiferous tubules is activated predominantly in Sertoli cells (Garcia & Hofmann, 2013;Liu et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Notch signaling regulates nuclear androgen receptor AR and membrane androgen receptor ZIP9 in mouse Sertoli cells

et al. 2019

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Background Notch signaling pathway is involved in contact‐dependent communication between the cells of seminiferous epithelium, and its proper activity is important for undisturbed spermatogenesis. Objectives The aim was to assess the effect of Notch pathway inhibition on the expression of nuclear (AR) and membrane (ZIP9) androgen receptors and androgen‐regulated genes, claudin‐5 and claudin‐11, in TM4 mouse Sertoli cell line. Materials and methods DAPT (γ‐secretase inhibitor) treatment and recombination signal binding protein silencing were employed to reduce Notch signaling, whereas immobilized ligands were used to activate Notch pathway in TM4 cells. To reveal specific effect of each androgen receptor, AR or ZIP9 silencing was performed. Results Notch pathway inhibition increased the expression of AR and ZIP9 mRNA and proteins (p < 0.01; p < 0.05) in TM4 cells, whereas incubation with Notch ligands, rDLL1 or rJAG1, reduced AR (p < 0.01; p < 0.001) and ZIP9 (p < 0.05; p < 0.01) expressions, respectively. Testosterone enhanced the expression of both receptors (p < 0.05; p < 0.01). Androgen‐regulated claudin‐5 and claudin‐11 (p < 0.01; p < 0.001) and cAMP (p < 0.001) were elevated in Notch‐inhibited cells, while activation of Notch signaling by DLL1 or JAG1 reduced claudin‐11 or claudin‐5 level (p < 0.01; p < 0.001), respectively. Discussion Our findings indicate opposite effect of Notch and androgen signaling on the expression of androgen receptors in TM4 cells. We demonstrated that AR expression is regulated by DLL1‐mediated Notch signaling, whereas JAG1 is involved in the regulation of ZIP9. The expression of both claudins and cAMP production is under inhibitory influence of Notch pathway. The effects of Notch signaling on claudin‐5 and claudin‐11 expression are mediated by ZIP9 and AR, respectively. Conclusion Notch signaling may be considered as an important pathway controlling Sertoli cell physiology, and its alterations may contribute to disturbed response of Sertoli cells to androgens.

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Section: Introductionmentioning

confidence: 99%

Notch signaling regulates nuclear androgen receptor AR and membrane androgen receptor ZIP9 in mouse Sertoli cells

et al. 2019

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“…This is being complemented by lineage tracing analyses performed by Silvia Fre (Institute Curie, France) in the mammary gland. The recently generated Notch1 activity trap mouse line (Liu et al, 2015a) will further help to map signalreceiving cells.…”

Section: Notch-mediated Regulation Of Cell State and Fatementioning

confidence: 99%

The Notch meeting: an odyssey from structure to function

Chitnis

Bally‐Cuif

2016

Development

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There was an error published in Development 143, 547-553.The name of the second author was spelt incorrectly. This error has now been corrected in the print, online and PDF versions of the paper.We apologise to the authors for this mistake. 1229 ABSTRACTThe Notch signaling pathway plays fundamental roles in diverse developmental processes. Studies of the basic biology of Notch function have provided insights into how its dysfunction contributes to multi-systemic diseases and cancer. In addition, our understanding of Notch signaling in maintaining stem/progenitor cell populations is revealing new avenues for rekindling regeneration. The Notch IX meeting, which was held in Athens, Greece in October 2015, brought together scientists working on different model systems and studying Notch signaling in various contexts. Here, we provide a summary of the key points that were presented at the meeting. Although we focus on the molecular mechanisms that determine Notch signaling and its role in development, we also cover talks describing roles for Notch in adulthood. Together, the talks revealed how interactions between adjacent cells mediated by Notch regulate development and physiology at multiple levels.

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“…To demarcate cells where Notch1 signaling has been active during development, we performed lineage-tracing experiments in mice where the Notch1 activity-trap line is combined with the TdTomato reporter allele ( N1IP::CreHI; TdTom , Supplemental Figure IA 16 ). Clusters of atrial cardiomyocytes within right and left atria are labeled (Supplemental Figure IB–G), indicative of active myocardial Notch signaling, and consistent with previous reports delineating active Notch signaling within embryonic atrial cardiomyocytes using immunohistochemical methods to detect the Notch1 intracellular domain (NICD) 15 .…”

Section: Resultsmentioning

confidence: 99%

“…αMHC-rtTA 63 , tetO_NICD 64 , tdTomato 65 , N1IP::Cre HI 16 , Cntn2-eGFP 66 , Hcn4CreERT2 28 , and R26R NICD 67 mice have been described previously, and were maintained on a mixed genetic background. For experiments involving conditional gene expression, induction of NICD expression was accomplished with doxycycline chow during the stated time points.…”

Section: Methodsmentioning

confidence: 99%

Transient Notch Activation Induces Long-Term Gene Expression Changes Leading to Sick Sinus Syndrome in Mice

Qiao

Lipovsky

Hicks

et al. 2017

Circulation Research

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Rationale Notch signaling programs cardiac conduction during development, and in the adult ventricle, injury-induced Notch reactivation initiates global transcriptional and epigenetic changes. Objective To determine whether Notch reactivation may stably alter atrial ion channel gene expression and arrhythmia inducibility. Methods and Results To model an injury response and determine the effects of Notch signaling on atrial electrophysiology, we transiently activate Notch signaling within adult myocardium using a doxycycline-inducible genetic system (iNICD). Significant heart rate slowing and frequent sinus pauses are observed in iNICD mice when compared with controls. iNICD mice have structurally normal atria and preserved sinus node architecture, but expression of key transcriptional regulators of sinus node and atrial conduction, including Nkx2-5, Tbx3 and Tbx5 are dysregulated. To determine whether the induced electrical changes are stable, we transiently activated Notch followed by a prolonged washout period and observed that, in addition to decreased heart rate, atrial conduction velocity is persistently slower than control. Consistent with conduction slowing, genes encoding molecular determinants of atrial conduction velocity, including Scn5a (Nav1.5) and Gja5 (connexin 40), are persistently down-regulated long after a transient Notch pulse. Consistent with the reduction in Scn5a transcript, Notch induces global changes in the atrial action potential, including a reduced dVm/dtmax. In addition, programmed electrical stimulation near the murine pulmonary vein demonstrates increased susceptibility to atrial arrhythmias in mice where Notch has been transiently activated. Taken together, these results suggest that transient Notch activation persistently alters ion channel gene expression and atrial electrophysiology, and predisposes to an arrhythmogenic substrate. Conclusions Our data provide evidence that Notch signaling regulates transcription factor and ion channel gene expression within adult atrial myocardium. Notch reactivation induces electrical changes resulting in sinus bradycardia, sinus pauses and a susceptibility to atrial arrhythmias, which contribute to a phenotype resembling sick sinus syndrome.

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Second-generation Notch1 activity-trap mouse line (N1IP::CreHI) provides a more comprehensive map of cells experiencing Notch1 activity

Abstract: We have previously described the creation and analysis of a Notch1 activity-trap mouse line, Notch1 intramembrane proteolysis-Cre6MT or N1IP::Cre LO

Cited by 20 publications

References 68 publications

Notch signaling regulates nuclear androgen receptor AR and membrane androgen receptor ZIP9 in mouse Sertoli cells

Notch signaling regulates nuclear androgen receptor AR and membrane androgen receptor ZIP9 in mouse Sertoli cells

The Notch meeting: an odyssey from structure to function

Transient Notch Activation Induces Long-Term Gene Expression Changes Leading to Sick Sinus Syndrome in Mice

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