Deficient T Cell Fate Specification in Mice with an Induced Inactivation of Notch1

Radtke, Freddy; Wilson, Anne; Stark, Gerlinde; Bauer, Michelle J; Meerwijk, Joost P. M. van; MacDonald, H. Robson; Aguet, Michel

doi:10.1016/s1074-7613(00)80054-0

Cited by 1,274 publications

(1,175 citation statements)

References 54 publications

Supporting

Mentioning

1,089

Contrasting

Unclassified

Order By: Relevance

“…To determine the specific cell lineage in which loss of Notch1 contributes to the aortic valve phenotype in Notch1 +/− ;Nos3 −/− mice, we used mice containing a Notch1 ‐floxed allele 26. Because Notch1 is expressed throughout the developing valve mesenchyme in all of the aforementioned lineages, we used Cre‐specific drivers for each cell lineage.…”

Section: Resultsmentioning

confidence: 99%

Endothelial Notch1 Is Required for Proper Development of the Semilunar Valves and Cardiac Outflow Tract

Koenig

Bosse

Majumdar

et al. 2016

JAHA

Self Cite

View full text Add to dashboard Cite

BackgroundCongenital heart disease is the most common type of birth defect, affecting ≈2% of the population. Malformations involving the cardiac outflow tract and semilunar valves account for >50% of these cases predominantly because of a bicuspid aortic valve, which has an estimated prevalence of 1% in the population. We previously reported that mutations in NOTCH1 were a cause of bicuspid aortic valve in nonsyndromic autosomal‐dominant human pedigrees. Subsequently, we described a highly penetrant mouse model of aortic valve disease, consisting of a bicuspid aortic valve with thickened cusps and associated stenosis and regurgitation, in Notch1‐haploinsufficient adult mice backcrossed into a Nos3‐null background.Methods and ResultsHere, we described the congenital cardiac abnormalities in Notch1 +/− ;Nos3 −/− embryos that led to ≈65% lethality by postnatal day 10. Although expected Mendelian ratios of Notch1 +/− ;Nos3 −/− embryos were found at embryonic day 18.5, histological examination revealed thickened, malformed semilunar valve leaflets accompanied by additional anomalies of the cardiac outflow tract including ventricular septal defects and overriding aorta. The aortic valve leaflets of Notch1 +/− ;Nos3 −/− embryos at embryonic day 15.5 were significantly thicker than controls, consistent with a defect in remodeling of the semilunar valve cushions. In addition, we generated mice haploinsufficient for Notch1 specifically in endothelial and endothelial‐derived cells in a Nos3‐null background and found that Notch1 fl/+;Tie2‐Cre +/− ;Nos3 −/− mice recapitulate the congenital cardiac phenotype of Notch1 +/− ;Nos3 −/− embryos.ConclusionsOur data demonstrate the role of endothelial Notch1 in the proper development of the semilunar valves and cardiac outflow tract.

show abstract

Section: Resultsmentioning

confidence: 99%

Endothelial Notch1 Is Required for Proper Development of the Semilunar Valves and Cardiac Outflow Tract

Koenig

Bosse

Majumdar

et al. 2016

JAHA

Self Cite

View full text Add to dashboard Cite

show abstract

“…On the other hand, none of the loss-of-function studies have demonstrated a role for the Notch/RBP-J signaling pathway in hematopoietic stem cell maintenance. Neither inducible knock-out of RBP-J [68], Notch1 [134] or Jagged1 [135] have led to a reduction of hematopoietic stem cells. In addition, Pear and colleagues showed that HSCs that carry dominantnegative mastermind (dnMAML) can engraft normally in bone-marrow transplantation assays, and that normal frequencies in long-term reconstitution assays are achieved in both the presence or absence of dnMAML [136].…”

Section: Notch In Hematopoiesismentioning

confidence: 99%

“…The importance of Notch signaling for the induction of Tcell fate was first demonstrated in mice in which the Notch1 gene was conditionally deleted using Mx-Cre. These mice exhibited a complete block in T-cell development at an early stage of differentiation and an emergence of ectopic B-cell development in the thymus [134]. Conversely, overexpression of constitutive-active Notch (NICD) in the bone marrow instructed a T-cell fate in bone marrow progenitors and inhibited B-cell development [137].…”

Section: T-cell Developmentmentioning

confidence: 99%

The Notch signaling pathway: Transcriptional regulation at Notch target genes

Borggrefe

Oswald

2009

Cell. Mol. Life Sci.

584

499

View full text Add to dashboard Cite

. The Notch gene encodes a transmembrane receptor that gave the name to the evolutionary highly conserved Notch signaling cascade. It plays a pivotal role in the regulation of many fundamental cellular processes such as proliferation, stem cell maintenance and differentiation during embryonic and adult development. After specific ligand binding, the intracellular part of the Notch receptor is cleaved off and translocates to the nucleus, where it binds to the transcription factor RBP-J. In the absence of activated Notch, RBP-J represses Notch target genes by recruiting a corepressor complex. Here, we review Notch signaling with a focus on gene regulatory events at Notch target genes. This is of utmost importance to understand Notch signaling since certain RBP-J associated cofactors and particular epigenetic marks determine the specificity of Notch target gene expression in different cell types. We subsequently summarize the current knowledge about Notch target genes and the physiological significance of Notch signaling in development and cancer.

show abstract

“…For example, this pathway plays an essential role in T cell development; In the absence of either Notch1 or Hes1, T cell development is arrested at the earliest phase before T cell receptor gene rearrangement, indicating that both Notch1 and Hes1 are essential for T cell fate specification [25], [26]. In addition, both Notch1 and Hes1 also regulate later stages of T cell development such as generation of CD8 single-positive cells from CD4CD8 double-positive cells [27], [28].…”

Section: The Notch-hes Pathway In Other Cell Typesmentioning

confidence: 99%

The Notch-Hes pathway in mammalian neural development

1999

View full text Add to dashboard Cite

A wide variety of neurons and glial cells differentiate from common precursor cells in the developing nervous system. During this process, Notch-mediated cell-cell interaction is essential for maintenance of dividing cells and subsequent generation of cell type diversity. Activation of Notch inhibits cellular differentiation, and abnormality of the Notch pathway leads to premature neuronal differentiation, the lack of some cell types, and severe defects of tissue morphogenesis. Recent data demonstrate that Notch fails to inhibit cellular differentiation in the absence of the bHLH genes Hes1 and Hes5, which functionally antagonize the neuronal bHLH genes such as Mash1. These results indicate that the two Hes genes are essential effectors for the Notch pathway and that neuronal differentiation is controlled by the pathway "Notch-Hes1/ Hes5-|Mash1".

show abstract

Deficient T Cell Fate Specification in Mice with an Induced Inactivation of Notch1

Cited by 1,274 publications

References 54 publications

Endothelial Notch1 Is Required for Proper Development of the Semilunar Valves and Cardiac Outflow Tract

Endothelial Notch1 Is Required for Proper Development of the Semilunar Valves and Cardiac Outflow Tract

The Notch signaling pathway: Transcriptional regulation at Notch target genes

The Notch-Hes pathway in mammalian neural development

Contact Info

Product

Resources

About