Postnatal Notch1 activation induces T‑cell malignancy in conditional and inducible mouse models

The Notch1 signaling pathway is essential for hematopoietic development. However, the effects of postnatal activation of Notch1 signaling on hematopoietic system is not yet fully understood. We previously generated ZEG‑IC‑Notch1 transgenic mice that have a floxed β‑geo/stop signal between a CMV promoter and intracellular domain of Notch1 (IC‑Notch1). Constitutively active IC‑Notch1 is silent until the introduction of Cre recombinase. In this study, endothelial/hematopoietic specific expression of IC‑Notch1 in double transgenic ZEG‑IC‑Notch1/Tie2‑Cre embryos induced embryonic lethality at E9.5 with defects in vascular system but not in hematopoietic system. Inducible IC‑Notch1 expression in adult mice was achieved by using tetracycline regulated Cre system. The ZEG‑IC‑Notch1/Tie2‑tTA/tet‑O‑Cre triple transgenic mice survived embryonic development when maintained on tetracycline. Post‑natal withdrawal of tetracycline induced expression of IC‑Notch1 transgene in hematopoietic cells of adult mice. The triple transgenic mice displayed extensive T‑cell infiltration in multiple organs and T‑cell malignancy of lymph nodes. In addition, the protein levels of p53 and alternative reading frame (ARF) were decreased in lymphoma‑like neoplasms from the triple transgenic mice while their mRNA expression remained unchanged, suggesting that IC‑Notch1 might repress ARF‑p53 pathway by a post‑transcriptional mechanism. This study demonstrated that activation of constitutive Notch1 signaling after embryonic development alters adult hematopoiesis and induces T‑cell malignancy.

Constitutive notch signaling in adult transgenic mice inhibits bFGF-induced angiogenesis and blocks ovarian follicle development

Notch signaling is important in angiogenesis during embryonic development. However, the embryonic lethal phenotypes of knock-out and transgenic mice have precluded studies of the role of Notch post-natally. To develop a mouse model that would bypass the embryonic lethal phenotype and investigate the possible role of Notch signaling in adult vessel growth, we developed transgenic mice with Cre-conditional expression of the constitutively active intracellular domain of Notch1 (IC-Notch1). Double transgenic IC-Notch1/Tie2-Cre embryos with endothelial specific IC-Notch1 expression died at embryonic day 9.5. They displayed collapsed and leaky blood vessels and defects in angiogenesis development. A tetracycline-inducible system was used to express Cre recombinase postnatally in endothelial cells. In adult mice, IC-Notch1 expression inhibited bFGF-induced neovascularization and female mice lacked mature ovarian follicles, which may reflect the block in bFGF-induced angiogenesis required for follicle growth. Our results demonstrate that Notch signaling is important for both embryonic and adult angiogenesis and indicate that the Notch signaling pathway may be a useful target for angiogenic therapies.

Das Altfranzösische aus Raschi's Bibelcommentar

von M. Grünwald

Über den jüdisch-spanischen Dialekt

Text deutsch u. teilw. span. u. hebr.

Hebräisch-deutsche-Vorlegeblätter zur Hebräisch-deutschen Schön- und Rechtschreibung nach den Regeln der deutschen Sprache : bearbeitet für Bürger- u. Landschulen auch für Erwachsene ...

von Salomon Eichberg, jun. u. Isaac Ochs

Biblisches Lehrbuch der hebräischen Sprache nach der Hamilton'schen Interlinearmethode

bearb. von Creizenach

Das Gebet-"Übersetzen" als Gebet-"Unterricht" : ein Leitfaden für Schule und Haus nach den Grundsätzen der Herbart-Ziller'schen Interesse-Bildung

von J. Goldschmidt, Rabbiner in Offenbach a. M.

Festschrift zum 50jährigen Bestehen des Rabbinerseminars zu Berlin : 1873-1923, 5634-5684

hrsg. von den Dozenten

Heinrich Graetz : a centenary

by Gotthard Deutsch

"Ozar Sefath Kodesch" : vollständiges, kurzgefaßtes Wörterbuch der ebräischen Sprache mit Angabe aller in der heiligen Schrift gebräuchlichen Conjugationen ; zum Gebrauche für Schulen und Laien ; ebräisch-deutscher Theil

von M. E. Stern

Arukh he-ḥadash

bearb. von Gustaf H. Dalman

Lexikalische Untersuchungen zur Sprache der jerusalemischen Pentateuch-Targume

von M.Neumark

Šaʿašûaʿ nôʿar : ein lehrreiches jidiš-daiṭšes lezebuch fir di jugend

Digitalisat der Ausg. Wien, 1815