Analysis of HeyL expression in wild-type and Notch pathway mutant mouse embryos

Abstract

In vertebrates Notch signaling regulates cell fate decisions and boundary formation and it underlies several murine and human diseases. Gene targeting experiments point to key roles of Notch receptors, ligands, modulators and downstream targets in somitogenesis, neurogenesis and vascular development. Here we report the embryonic expression of the hairy-related basic helix-loop-helix gene HeyL in wild-type and Notch pathway mutant mice. We show that HeyL is strongly expressed in the presomitic mesoderm, the somites, the peripheral nervous system and smooth muscle of all arteries. Loss of HeyL expression at the level of nascent somites in Notch1 and Delta-like1 knockout mutants implicates HeyL as a Notch effector during somite formation. Furthermore, HeyL expression in vascular smooth muscle cells and in the thymus strikingly overlaps with that of Notch3, mutations of which underlie the CADASIL vascular disorder.

Context-Dependent Sensitivity to Mutations Disrupting the Structural Integrity of Individual EGF Repeats in the Mouse Notch Ligand DLL1

“…To compare the impact of EGF repeat mutations on somitogenesis, we analyzed expression of the Notch target HeyL (Leimeister et al 2000), and Uncx4.1 and Tbx18, markers for posterior and anterior somite compartments, respectively, in E9.5 embryos (Neidhardt et al 1997;Kraus et al 2001). The expression patterns of these genes as well as the axial skeletons of homozygous Dll1 Dll1wt ( Figure 3A, e-h) and Dll1 EGF6m ( Figure 3A, zd-zg) embryos were indistinguishable from wild type ( Figure 3A, a-d).…”

Gamma secretase inhibitor blocks Notch activation and induces apoptosis in Kaposi's sarcoma tumor cells

“…Although the KS-associated herpesvirus (KSHV; also known as human herpesvirus 8, HHV-8) has been identified as the likely etiologic agent responsible for KS, it is currently unknown how KSHV infection leads to KS from a pathophysiological perspective. To date, Notch expression has not been studied in KS; however, endothelial cells (ECs), the precursor of KS cells, are known to express Notch-1, -2, and -4 as well as the ligands Jagged-1, -2, and Dll-1, -4 (Uyttendaele et al, 1996;Luo et al, 1997;Leimeister et al, 2000;Shutter et al, 2000;Tsai et al, 2000;Villa et al, 2001). In addition, Notch signaling has been shown to be essential for normal vascular development, and targeted disruption of Notch-1, Notch-1/Notch-4, Jagged-1 or Dll-1 in ECs results in the in utero demise of the embryo due to vascular defects and hemorrhage (Hrabe de Angelis et al, 1997;Xue et al, 1999;Huppert et al, 2000).…”

Notch signaling during vascular development

“…To date, four Notch family receptors and five ligands have been described in mammals. Evidence that the Notch pathway plays a critical role in vascular development and homeostasis includes the specific expression of Notch pathway ligands and receptors in vascular endothelium or supporting cells (7)(8)(9)(10)(11)(12)(13)(14), as well as the phenotypes of several targeted mutants in Notch pathway components. These mutants, which include mutations in genes encoding both ligands and receptors, die during embryogenesis from hemorrhaging because of defects in vascular morphogenesis (15)(16)(17).…”