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⇱ Human ligands of the Notch receptor - PubMed

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Abstract

During development, the Notch signaling pathway is essential for the appropriate differentiation of many cell types in organisms across the phylogenetic scale, including humans. Notch signaling is also implicated in human diseases, including a leukemia and two hereditary syndromes known as Alagille and CADASIL. To generate tools for pursuing the role of the Notch pathway in human disease and development, we have cloned and analyzed the expression of three human homologues of the Notch ligands Delta and Serrate, human Jagged1 (HJ1), human Jagged2 (HJ2), and human Delta1 (H-Delta-1), and determined their chromosomal localizations. We have also raised antibodies to HJ1, and used these antibodies in conjunction with in situ hybridization to examine the expression of these ligands in normal and cancerous cervical tissue. We find that, as reported previously for Notch, the ligands are up-regulated in certain neoplastic tissues. This observation is consistent with the notion that Notch signaling is an important element in these pathogenic conditions, raising the possibility that modulation of Notch activity could be used to influence the fate of the cells and offering a conceivable therapeutic avenue.

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Figures

👁 Figure 1.
Figure 1.
The deduced amino acid sequence for H-Delta-1, shown in alignment with C-Delta-1, mouse Dll-1, and Xenopus Delta-1. Boxed and shaded residues are identical. Shaded unboxed residues are conserved. Dotted lines indicate the signal peptide and transmembrane regions. Dashed line marks the DSL domain. Solid lines demarcate EGF repeats.
👁 Figure 2.
Figure 2.
Northern blots. A–C: H-Delta-1 and HJ1 and HJ2, respectively. The sizes of the labeled bands are given in the figure.
👁 Figure 3.
Figure 3.
Anti-HJ1 antibody TS1. a: Western blot demonstrates specific labeling of band at 130 kd. The first two lanes represent untransfected HaCat cells and ones transfected with empty vector, respectively. Three independently transfected HaCat cell lines, 14, 23, and 26, were tested, and all expressed a specifically labeled 130-kd band. b: rat polyclonal labeling of HaCaT cells co-transfected with HJ1 and intracellular Notch cDNA. Notch is labeled red and HJ1 green. Only cells that were immunoreactive for the Notch antibody were also labeled with TS1, showing that there was no nonspecific cross-reactivity with untransfected cells in culture. Original magnification, ×650.
👁 Figure 4.
Figure 4.
Expression of Notch and its ligands in squamous metaplasia of the uterine cervix. a: Notch2. Cervical sections reacted with anti-Notch antibody. Both the columnar epithelium, which is unstained except for the basal reserve cells, and the metaplastic tissue can be seen in this view. Note the sharp border between the strongly stained metaplastic squamous cells and the columnar cells epithelium (arrow). b; Immature squamous metaplasia immunolabeled for HJ1. HJ1 is strongly expressed only in the metaplastic tissue. c: In situ hybridization for H-Delta-1 shows patchy expression. d: In situ hybridization for HJ2 is negative in squamous metaplasia. Original magnification, ×300.
👁 Figure 5.
Figure 5.
Expression of Notch and its ligands in squamous cell carcinoma of the uterine cervix is up-regulated. a: Notch2, immunohistochemistry; b: HJ1, immunohistochemistry; c: H-Delta-1,; in situ hybridization; d: HJ2, in situ hybridization. Note in a–d the presence of unlabeled normal cervical glands. e, f: Double-labeled fluorescent photomicrographs of squamous carcinomas. Anti-Notch1 antibodies are shown in red; anti-HJ1 labeling is shown in green. Overlapping regions are yellow and include virtually all of the labeled tissue. Original magnification, ×300.
👁 Figure 6.
Figure 6.
Expression of Notch, HJ1, and H-Delta-1 in cervical adenocarcinoma is up-regulated. a: Notch1, immunohistochemistry; b: HJ1, immunohistochemistry; c: H-Delta-1, in situ hybridization. d: HJ1, in situ hybridization. Original magnification, ×300.
👁 Figure 7.
Figure 7.
Chromosomal localizations identified by FISH. a: H-Delta-1 is localized to 6q27. b: HJ1 is localized to 20p11–12. c: HJ2 is localized to 14q32.

References

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