Embryonic lethality and vascular defects in mice lacking the Notch ligand Jagged1
Embryonic lethality and vascular defects in mice lacking the Notch ligand Jagged1
Yingzi Xue1,2,+,[Dagger], Xiang Gao1,+,§, Claire E. Lindsell3, Christine R. Norton1, Bo Chang1, Carol Hicks3, Maureen Gendron-Maguire1,¶, Elizabeth B. Rand4, Gerry Weinmaster3 and Thomas Gridley1,*
1The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609-1500, USA, 2Department of Biological Sciences, Columbia University, New York, NY 10027, USA, 3Department of Biological Chemistry, UCLA School of Medicine, Los Angeles, CA 90024, USA and 4Division of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
Received November 6, 1998;Revised and Accepted February 4, 1999
The Notch signaling pathway is an evolutionarily conserved intercellular signaling mechanism essential for embryonic development in mammals. Mutations in the human JAGGED1 (JAG1) gene, which encodes a ligand for the Notch family of transmembrane receptors, cause the autosomal dominant disorder Alagille syndrome. We have examined the in vivo role of the mouse Jag1 gene by creating a null allele through gene targeting. Mice homozygous for the Jag1 mutation die from hemorrhage early during embryogenesis, exhibiting defects in remodeling of the embryonic and yolk sac vasculature. We mapped the Jag1 gene to mouse chromosome 2, in the vicinity of the Coloboma (Cm) deletion. Molecular and complementation analyses revealed that the Jag1 gene is functionally deleted in the Cm mutant allele. Mice heterozygous for the Jag1 null allele exhibit an eye dysmorphology similar to that of Cm/+ heterozygotes, but do not exhibit other phenotypes characteristic of Cm/+ mice or of humans with Alagille syndrome. These results establish the phenotype of Cm/+ mice as a contiguous gene deletion syndrome and demonstrate that Jag1 is essential for remodeling of the embryonic vasculature.
The Notch signaling pathway is an evolutionarily conserved intercellular signaling mechanism and mutations in its components disrupt cell fate specification and embryonic development in organisms as diverse as insects, nematodes and mammals (reviewed in refs 1-3). Recent work has established that two human diseases are caused by mutations in components of the Notch signaling pathway. Mutations in the NOTCH3 gene cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL; OMIM 125310), an inherited vascular dementia syndrome (4). Mutations in the JAG1 gene, which encodes a ligand for Notch family receptors (5), cause Alagille syndrome (6,7). Alagille syndrome (OMIM 118450) is a pleiotropic developmental disorder that is one of the major forms of chronic liver disease in childhood. Alagille syndrome exhibits autosomal dominant inheritance and is characterized by neonatal jaundice and a paucity of intrahepatic bile ducts. Accompanying features of this syndrome include congenital heart defects, skeletal defects, ophthalmological abnormalities and characteristic facial appearance (reviewed in ref. 8). The mutations originally found in the JAG1 gene in Alagille syndrome patients were inactivating mutations, generally leading to premature truncation of the JAGGED1 protein (6,7). Surveys of the types and frequency of JAG1 mutation in Alagille syndrome patients revealed that patients with large deletions encompassing the entire JAG1 gene had the same phenotype as patients with intragenic JAG1 mutations, suggesting that haploinsufficiency for the JAG1 gene was the cause of Alagille syndrome (9,10). In this paper, we have examined the role of the mouse Jag1 gene by creating a null allele and have characterized embryos and mice homozygous and heterozygous for this mutation.
To analyze the in vivo role of the Jag1 gene, a targeting vector was constructed that deletes 5 kb of genomic sequence near the 5[prime]-end of the Jag1 gene (Fig. 1a). The targeted allele deletes the C-terminal portion of the DSL domain, which is required for interaction of ligands with Notch family receptors (2,11). We refer to this mutant allele as Jag1dDSL. The linearized targeting vector was electroporated into embryonic stem (ES) cells and germline transmission of the Jag1dDSL allele was obtained for two targeted clones (Fig. 1b). Mice heterozygous for the Jag1dDSL mutant allele were grossly normal, viable and fertile. RT-PCR and western blot analyses indicated that no Jag1 RNA or protein was detectable in Jag1dDSL/Jag1dDSL homozygous mutant embryos (Fig. 2).
Figure1. Targeted disruption of the mouse Jag1 gene. (a) Targeting scheme. The upper line shows the genomic organization of a portion of the Jag1 gene. Exons are indicated by black boxes. Additional exons are present 3[prime] of the exons indicated. The middle line represents the structure of the targeting vector. The bottom line shows the predicted structure of the Jag1 locus following homologous recombination of the targeting vector. Probes used for Southern blot analysis are indicated. Restriction enzymes: E, EcoRI; H, HindIII; K, KpnI; S, StuI. (b) DNA isolated from embryos of the intercross of Jag1dDSL/+ heterozygous mice was digested with EcoRI, blotted and hybridized with the indicated probe. Genotypes of progeny are indicated at the top of the lane.
Figure2. Analysis of Jag1 gene products by RT-PCR and western blot. (a) RT-PCR analysis of RNA isolated from embryos at E10. Primers used were specific for Jag1 and for peptidylprolyl isomerase B (Ppib) (used as a positive control). (b) Western blot analysis. The three left lanes are E10.5 embryo extracts with the indicated genotypes; the right two lanes are extracts from control and Jag1 transfected cell lines. The arrow indicates the size of full-length Jagged1 protein. L, L cells; JL, L cells transfected with Jag1 expression plasmid.
To examine whether animals homozygous for the Jag1dDSL mutation were viable, heterozygous F1 animals were intercrossed and genotypes of the F2 progeny determined 2-3 weeks after birth. No homozygotes were detected, indicating that the Jag1dDSL allele is a recessive lethal mutation. To determine when homozygous mutant embryos were dying, embryos were isolated from timed matings. At embryonic day (E)10.5, Jag1dDSL/Jag1dDSL homozygotes could be identified easily due to hemorrhaging and the presence of yolk sacs lacking large blood vessels (Fig. 3a and b). Histological analysis confirmed widespread hemorrhage, in particular in the cranial mesenchyme (Fig. 3c and d). When isolated at E11.5, homozygous mutant embryos were either completely resorbed or were severely necrotic, while at E9.5 homozygous mutant embryos could not usually be distinguished from wild-type and heterozygous littermates (data not shown).
Figure3. Vascular defects in Jag1dDSL mutant homozygotes. (a-j) Wild-type embryos are shown in the left column, Jag1dDSL/Jag1dDSL homozygous mutant embryos in the right column. (a and b) Whole mounts of E10.5 embryos and yolk sacs. Arrow indicates cranial hemorrhage in the mutant embryo. The yolk sac of the mutant is pale and lacks obvious large blood vessels. (c and d) Histological analysis reveals a large hemorrhage (arrow) adjacent to the optic vesicle in the mutant embryo. (e-j) PECAM-1 stained yolk sacs and embryos. (e and f) The mutant yolk sac has failed to remodel the primary vascular plexus to form large blood vessels. (g and h) The vascular network overlying the forebrain vesicles is less intricate in the mutant embryo. (i and j) The vessels in the head of the mutant embryo have a reduced diameter and an abnormal appearance. (k) Whole mount in situ hybridization with a Jag1 antisense riboprobe of an E10.5 wild-type embryo. Jag1 expression can be observed in cranial blood vessels (arrow). A `salt and pepper' pattern of Jag1 expression in the neuroepithelium is also observed.
We visualized the vascular network of Jag1dDSL/Jag1dDSL embryos and littermate controls in whole mount preparations by staining with a monoclonal antibody to platelet endothelial cell adhesion molecule-1 (PECAM-1), which is a specific marker for vascular endothelial cells (12). Defects in formation of the vascular system were observed both in the yolk sac and in the embryo of Jag1dDSL/Jag1dDSL homozygotes. Large vitelline blood vessels were present in the yolk sacs of control littermates, but large blood vessels were not present in the yolk sacs of Jag1dDSL/Jag1dDSL homozygous mutant embryos (Fig. 3e and f). The cranial region of the homozygous mutant embryos also exhibited vascular defects. The vascular network overlying the forebrain of the mutant embryos was not as intricate as that of heterozygous and wild-type littermates (Fig. 3g and h). Large blood vessels of the head had an abnormal appearance and a reduced diameter in the Jag1dDSL/Jag1dDSL homozygous mutant embryos (Fig. 3i and j).
Several groups have previously documented expression of the Jag1 gene (also referred to as the Serrate1 gene) in blood vessels in chick and mouse embryos (13-15). However, Jag1 expression in cranial blood vessels that appear to be the first site of hemorrhage in Jag1dDSL/Jag1dDSL homozygous mutant embryos had not been reported. In situ hybridization of E10.5 wild-type embryos revealed Jag1 expression in cranial blood vessels (Fig. 3k).
Recent work has demonstrated that mutations in components of the Notch signaling pathway cause defects in segmentation and somite formation in mice (16-21). Since the Jag1 gene is expressed in the forming somite (13,21,22), we analyzed Jag1dDSL/Jag1dDSL homozygous mutant embryos with several markers expressed in somites and in unsegmented paraxial mesoderm, including the genes Dll1 (23), Dll3 (24), Lunatic fringe (Lfng; 21) and Uncx4.1 (25). This analysis revealed no detectable defects in segmentation in the Jag1dDSL/Jag1dDSL mutant embryos (Fig. 4).
Figure4.Jag1dDSL mutant homozygotes do not exhibit defects in segmentation. Whole mount in situ hybridization with the indicated probes to embryos isolated at E9.5. Wild-type embryos are shown in the left column, Jag1dDSL/Jag1dDSL homozygous mutant embryos in the right column. (a and b) Uncx4.1 probe;(c and d) Dll1 probe; (e and f) Dll3 probe; (g and h) Lfng probe.
We mapped the chromosomal location of the Jag1 gene by interspecific backcross analysis to distal chromosome 2 (Fig. 5), close to the semidominant Coloboma (Cm) mutation (26). Cm/+ mice display several defects, including ophthalmic dysmorphology (e.g. iris colobomas), head bobbing, circling and profound hyperactivity (27). Molecular analysis has revealed that Cm is a 1-2 cM deletion (26).
Figure5.Jag1 chromosomal mapping. (a) Localization of Jag1 to mouse chromosome 2. A partial chromosome 2 linkage map showing the location of Jag1 in relation to linked markers is shown. To the left of the chromosome is shown the cM position for these loci, as well as the cM positions for two loci not mapped in this cross, Cm and Snap25. (b) Haplotype figure showing part of chromosome 2 with loci linked to Jag1. The black boxes represent the C57BL6/JEi allele and the white boxes the SPRET/Ei allele. The percentage recombination (R) between adjacent loci is given to the right of the figure, with the standard error (SE).
To test whether the Jag1 gene mapped within the Cm deletion, we crossed a male Cm/+ hemizygote with Jag1dDSL/+ female heterozygotes and isolated embryos at E10.5. Four out of 15 embryos from two different litters exhibited cranial hemorrhaging identical to Jag1dDSL/Jag1dDSL homozygous mutant embryos (Fig. 6b-d). When yolk sac DNA isolated from these abnormal embryos was genotyped with allele-specific PCR primers, the Jag1dDSL mutant allele-specific primers amplified a band of the correct size, but the Jag1 wild-type allele-specific primers did not amplify any band (Fig. 6a). This indicated that the portion of the Jag1 gene defined by our wild-type allele-specific PCR primers (the region encoding the DSL domain of the JAG1 protein) is deleted on the Cm chromosome. We have not determined if the entire coding sequence of the Jag1 gene is deleted on the Cm chromosome.
Figure6. Deletion of the Jag1 gene on the Cm chromosome. (a) PCR genotyping of embryos from the intercross of a Cm/+ male and a Jag1dDSL/+ female. White arrows indicate embryos (nos 1 and 5) that did not amplify the wild-type Jag1 band. These embryos were hemorrhagic; all other embryos in this litter had a wild-type morphology. (b-d) Whole mount morphology of embryos isolated at E10.5. (b) Wild-type; (c) Jag1dDSL/Jag1dDSL; (d) Jag1dDSL/Cm; (e) Cm/Cm. Black arrows indicate areas of hemorrhage in Jag1dDSL/Jag1dDSL, Jag1dDSL/Cm and Cm/Cm embryos.
In a previous study, Theiler and Varnum (28) had examined embryos from the intercross of Cm/+ heterozygotes between E6.0 and E9.5 and concluded from this analysis that Cm/Cm homozygotes died before day 6 of gestation. However, Jag1dDSL/Jag1dDSL homozygous mutant embryos are generally not apparent phenotypically until ~E10.5. We therefore examined embryos from the intercross of Cm/+ heterozygotes at E10.5. We isolated 38 embryos from five different litters of Cm/+ intercrosses. Ten out of 38 (26%) of these embryos were hemorrhagic (Fig. 6e) and PCR analysis indicated that these embryos were Cm/Cm homozygotes (data not shown; see Materials and Methods). These results demonstrate that Cm/Cm homozygous mutant embryos do not die prior to E6, but die around E10.5 from vascular defects similar to those exhibited by Jag1dDSL/Jag1dDSL homozygous mutant embryos.
We examined Jag1dDSL/+ adult heterozygotes for phenotypic abnormalities, since both Alagille syndrome in humans and phenotypes associated with the Cm deletion in mice are inherited as semidominant mutations. The Jag1dDSL/+ mice exhibited an eye dysmorphology similar to that of Cm/+ mice (Table 1 and Fig. 7). The penetrance of the eye dysmorphology phenotype in Jag1dDSL/+ mice was high (~80%) on a mixed genetic background and increased to 100% on a predominantly C57BL/6J background (Table 1). However, the Jag1dDSL/+ heterozygotes did not appear to display the head bobbing, circling and hyperactivity characteristic of Cm/+ mice (27). Jag1dDSL/+ adult heterozygotes (n = 10) were examined for other phenotypic abnormalities associated with Alagille syndrome in humans (e.g. defects of the liver, heart and axial skeleton), but no defects in these structures were observed in the Jag1dDSL/+ mice.
Figure7. Eye dysmorphologies in Jag1dDSL/+ and Cm/+ mutant heterozygotes. (a) Wild-type; (b) iris coloboma in Cm/+ heterozygote; (c) iris coloboma in Jag1dDSL/+ heterozygote; (d) corneal opacity in Jag1dDSL/+ heterozygote. The white dot in each eye is a reflection from the lamp used for illumination.
In this report we have demonstrated that the Notch ligand encoded by the Jag1 gene plays an essential role during embryonic development in mice. Mice homozygous for a targeted null mutation of the Jag1 gene die at E10 due to vascular defects. During the early stages of vascular development in both the embryo and the yolk sac, endothelial cell precursors differentiate and coalesce into a network of homogeneously sized primitive blood vessels (the primary vascular plexus) in a process termed vasculogenesis. This primary vascular plexus is then remodeled into the large and small vessels of the mature vascular system by the process of angiogenesis (29,30). In the yolk sac of Jag1dDSL/Jag1dDSL homozygous mutant embryos, the primary vascular plexus appeared to form normally, indicating that there were no apparent defects in vasculogenesis in the homozygous mutants. However, the Jag1dDSL/Jag1dDSL homozygous mutant embryos failed to remodel the primary vascular plexus to form the large vitelline blood vessels, a process that occurs by angiogenesis. The cranial region of the homozygous mutant embryos also exhibited a defect in vascular remodeling. The vascular network overlying the forebrain of the mutant embryos was not as intricate as that of control littermates and the large blood vessels of the head had an abnormal appearance and a reduced diameter. These abnormalities suggest that the Jag1dDSL/Jag1dDSL homozygous mutant embryos exhibit defects in angiogenic vascular remodeling both in the yolk sac and in the embryo.
Zimrin et al. have previously demonstrated a connection between Jag1 expression and angiogenesis (31). They isolated the human Jag1 cDNA in a differential display screen for genes induced in an in vitro angiogenesis model and also showed that administration of Jag1 antisense oligonucleotides could modulate in vitro angiogenesis (31). Our results extend these findings by demonstrating that expression of the Jag1 gene plays an important role in vascular development during embryogenesis in mice, in particular during angiogenic vascular remodeling. Taken together with the finding that mutations of the human Notch3 gene cause the systemic vascular disease CADASIL (4), these results indicate that components of the Notch signaling pathway are essential both for vascular development in embryos and maintenance of a healthy vascular system in adults.
Recent work has demonstrated that mutations in components of the Notch signaling pathway cause defects in somite formation in mice. Notch pathway mutants exhibiting defects in somitogenesis include the genes encoding the Notch1 receptor (16,17), the ligands Dll1 (18) and Dll3 (19) and Lfng (20,21), which encodes a secreted protein that regulates Notch signaling (22,32). We analyzed Jag1dDSL/Jag1dDSL homozygous mutant embryos with several markers expressed in somites and in unsegmented paraxial mesoderm and found no detectable defects in segmentation in the homozygous mutant embryos. This result supports our previous finding that expression of the Jag1 gene in the forming somite is unaffected in Lfng-/- mutant embryos (21). We have also demonstrated previously that mice homozygous for a null mutation of the related Jagged2 (Jag2) gene, while displaying a variety of phenotypic defects, exhibit no defects in somite formation (33). These findings reveal a division of function among the Notch family ligands. Notch signaling mediated by the Delta family ligands encoded by the Dll1 and Dll3 genes is essential for proper somite formation, but signaling mediated by the Serrate family ligands encoded by the Jag1 and Jag2 genes is not required for somitogenesis in mice.
While our RT-PCR and western blot data indicated that the Jag1dDSL allele is most likely a null (amorphic) allele, the most stringent genetic test to determine whether a particular mutation is a null allele is to test that mutation over a deletion of the locus in question (34). Our finding that at least a portion of the Jag1 gene is deleted on the Cm mutant chromosome permitted us to perform this classic genetic test. Since the phenotype of the Jag1dDSL/Cm mutant embryos appeared identical to that of Jag1dDSL/Jag1dDSL homozygotes, this analysis confirmed that the targeted Jag1dDSL mutation is a null allele.
Since both Alagille syndrome in humans and phenotypes associated with the Cm deletion in mice are inherited as semidominant mutations, we examined Jag1dDSL/+ adult heterozygotes for phenotypic abnormalities. The Jag1dDSL/+ mice exhibited an eye dysmorphology similar to that of Cm/+ mice, but did not appear to display the head bobbing, circling and hyperactivity characteristic of Cm/+ mice (27). Similarly, Alagille syndrome patients often display ophthalmological abnormalities, typically including anterior chamber defects and posterior embryotoxon (8). The ophthalmological abnormalities displayed by the Jag1dDSL/+ adult heterozygotes are somewhat different in type and are more severe than the abnormalities typically displayed by Alagille syndrome patients. Both Jag1dDSL/+ and Cm/+ mice exhibit iris colobomas (Fig. 7). The iris, at its periphery, is continuous with the ciliary body. During development of the eye, the Jag1 gene is expressed in the ciliary body (35,36). While we do not currently understand at a mechanistic level how reduction of Jag1 gene dosage leads to the formation of iris colobomas, this phenotype correlates well with the pattern of expression of the Jag1 gene during eye development.
In contrast to the presence of eye dysmorphologies in the Jag1dDSL/+ heterozygotes, these mice did not appear to exhibit other phenotypic abnormalities (e.g. defects of the liver, heart and axial skeleton) associated with Alagille syndrome in humans. Phenotypes sensitive to gene dosage are characteristic of mutations of Notch pathway components in Drosophila (reviewed in ref. 37). The eye phenotype of the Jag1dDSL/+ mice is the first documented instance of a gene dosage-sensitive phenotype in any of the Notch pathway mutants in mice. However, the Jag1dDSL/+ mice do not appear to represent a good animal model for Alagille syndrome.
Several human disorders (termed contiguous gene deletion syndromes) are associated with either cytogenetically detectable or submicroscopic chromosomal deletions (38). In mice, the Cm deletion has been shown to encompass the genes encoding phospholipase C isoform [beta]-1 and the synaptosome-associated protein (25 kDa; Snap25) (26). Expression of a transgene encoding the SNAP25 protein rescues the hyperactivity of Cm/+ hemizygotes, but not the ophthalmic dysmorphology or head bobbing (27). Our molecular and genetic data indicate that the Cm deletion also encompasses at least a portion of the Jag1 gene and that loss of the Jag1 gene is responsible for the ophthalmic dysmorphology of Cm/+ hemizygotes. These data indicate that the phenotype of Cm/+ mice constitutes a contiguous gene deletion syndrome.
Genomic clones of the Jag1 gene were obtained by screening a P1 genomic library made from genomic DNA of 129/Sv strain mouse embryonic stem cells (Genome Systems, St Louis, MO) with PCR primers corresponding to sequences specific to the mouse Jag1 cDNA. Positive P1 clones were analyzed by restriction mapping and Southern hybridization. Fragments that hybridized to Jag1 cDNA clones were subcloned and the exon-intron organization of part of the Jag1 gene was determined by nucleotide sequencing.
The targeting vector was constructed from an 11 kb genomic subclone of the Jag1 gene. The 3[prime] arm was a 2.3 kb HindIII genomic fragment that was subcloned downstream of a PGK-neo expression cassette (39). To construct the 5[prime] arm, an oligonucleotide (5[prime]-AAGCAATTGCGCCAAAGCCATAG-3[prime]) complementary to a sequence in the middle of the exon encoding the DSL domain of the JAG1 protein was used as a PCR primer for amplification on a Jag1 genomic subclone. The amplified fragment was then subcloned upstream of the PGK-neo cassette. This disrupted the exon encoding the DSL domain and resulted in the deletion of a 5.0 kb genomic fragment containing the exons encoding the C-terminal half of the DSL domain and half of the first EGF repeat of the JAG1 protein. In this paper, we refer to this allele as Jag1dDSL (the nomenclature for this allele assigned by the International Committee on Standardized Genetics Nomenclature for Mice is Jag1tm1Grid ). A HSV-tk cassette (40) was also introduced to allow negative selection against random integration of the targeting vector.
CJ7 ES cells were electroporated with 25 µg of linearized targeting vector, selected, screened and injected into blastocysts from C57BL/6J mice as previously described (41). Animals were genotyped by Southern blot analysis or by PCR. PCR primers for the Jag1 wild-type allele were JG1 (5[prime]-TCTCACTCAGGCATGATAAACC-3[prime]) and JG2 (5[prime]-TAACGGGGACTCCGGACAGGG-3[prime]). Primers for the Jag1dDSL allele were JG1 and JG4 (5[prime]-GGTGCTGTCCATCTGCACGAG-3[prime]). For RT-PCR, the Jag1 primers were JGRT1 (5[prime]-AGTGCCCAGAGCTTGAACCG-3[prime]) and JGRT2 (5[prime]-CTAAGGCTGCCATCACCATTAGG-3[prime]). Control primers for peptidylprolyl isomerase B (Ppib) were (5[prime]-ATATGAAGGTGCTCTTCGCCGCCG-3[prime]) and (5[prime]-CATTGGTGTCTTTGCCTGCATTGGC-3[prime]).
Male Cm/+ heterozygous mice on the C3H/HeSnJ background were backcrossed for two generations to C57BL/6J mice. Cm/+ heterozygous adult progeny were genotyped by examination for the presence of iris colobomas. These Cm/+ heterozygotes were intercrossed, and progeny were isolated at E10.5. Embryos were fixed for morphological analysis and DNA was prepared from the yolk sac of each embryo. Yolk sac DNA was examined for the presence of the wild-type Jag1 gene by allele-specific PCR using the primers JG1 and JG2 (see above). Primers for the wild-type Notch2 gene, which is located on chromosome 3 (42), were used as a positive control for DNA integrity. Primers for the Notch2 wild-type allele were (5[prime]-TCTCCATATTGATGAGCCATGC-3[prime]) and (5[prime]-CCAGTGTGCCACAGGTAAGTG-3[prime]).
Polyclonal antiserum (J59) specific for the cytoplasmic domain of rat JAG1 was raised by immunizing a rabbit with a bacterially expressed protein consisting of amino acids 1101-1219 inclusive of rat JAG1 fused to glutathione S-transferase. Embryo lysates (at E10.5) were separated on 8% SDS-PAGE gels and transferred to PVDF membrane. The membrane was incubated with affinity purified J59 antiserum and with goat anti-rabbit-horseradish peroxidase conjugate (Cappel, Durham, NC). The horseradish peroxidase signal was detected using chemiluminescence substrate (ECL; Amersham, Arlington Heights, IL).
Embryos were dissected and DNA was prepared from the yolk sacs or tails for genotyping. Embryos for histological analysis were fixed in Bouin's fixative. Fixed embryos were dehydrated through graded alcohols, embedded in paraffin, sectioned and stained with hematoxylin and eosin. Embryos for in situ hybridization were fixed overnight at 4°C in 4% paraformaldehyde in phosphate-buffered saline (PBS). Embryos for immunohistochemistry were fixed in 4% paraformaldehyde in PBS and stained with a monoclonal anti-PECAM-1 antibody (Pharmingen, San Diego, CA). For analysis of Jag1dDSL/+ heterozygous adult mice, animals were examined with a slit lamp for eye defects. Livers and hearts from these Jag1dDSL/+ heterozygotes (which all displayed eye defects; n = 10 Jag1dDSL/+ heterozygotes) and from age-matched littermate controls were dissected, fixed in Bouin's fixative and sectioned. Skeletons were examined by X-ray analysis.
We determined the chromosomal location of the Jag1 gene by interspecific backcross analysis. C57BL/6J and M.spretus DNAs were digested with several enzymes and analyzed for informative restriction fragment length polymorphisms (RFLPs) by Southern blotting using a Jag1 genomic probe (a 2.2 kb EcoRI-StuI fragment). An EcoRV RFLP was then used to analyze Southern blots of EcoRV-digested DNA from 94 N2 progeny from the cross (C57BL/6JEi×SPRET/Ei)F1×SPRET/Ei from the Jackson Laboratory BSS interspecific backcross panel (43). The presence or absence of the C57BL/6J-specific EcoRV fragment was followed in the backcross mice. Raw typing data for this cross are available at http://www.jax.org/resources/documents/cmdata . Centimorgan postitions for Cm and Snap25 (which have not been mapped in the Jackson BSS backcross) were obtained from the Mouse Genome Database (http://www.informatics.jax.org/locus.html ).
We thank M. Wilson for helpful discussions, L. Rowe and M. Barter of the Jackson Laboratory Backcross DNA Panel Mapping Resource for advice and for providing the chromosome mapping figures, one of the anonymous reviewers for suggesting an additional experiment and S. Ackerman, M. Davisson and A. Gossler for comments on the manuscript. This work was supported by grants from the NIH (NS36437 and HD34883 to T.G.; NS31885 to G.W.; EY07758 to B.C.) and the March of Dimes Foundation (1-FY97-0193 to T.G.; 5-FY94-0757 to G.W.). This work was also supported by a grant from the National Cancer Institute (CA34196) to the Jackson Laboratory.
1. Artavanis-Tsakonas, S., Matsuno, K. and Fortini, M.E. (1995) Notch signaling. Science, 268, 225-232. MEDLINE Abstract
2. Weinmaster, G. (1997) The ins and outs of Notch signaling. Mol. Cell. Neurosci., 9, 91-102. MEDLINE Abstract
3. Gridley, T. (1997) Notch signaling in vertebrate development and disease. Mol. Cell. Neurosci., 9, 103-108. MEDLINE Abstract
4. Joutel, A., Corpechot, C., Ducros, A., Vahedi, K., Chabriat, K.H., Mouton, P., Alamowitch, S., Domenga, V., Cécillion, M., Maréchal, E., Maciazek, J., Vayssiére, C., Cruaud, C., Cabanis, E.-A., Ruchoux, M.M., Weissenbach, J., Bach, J.F., Bousser, M.G. and Tournier-Lasserve, E. (1996) Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature, 383, 707-710. MEDLINE Abstract
5. Lindsell, C.E., Shawber, C.J., Boulter, J. and Weinmaster, G. (1995) Jagged: a mammalian ligand that activates Notch1. Cell, 80, 909-917. MEDLINE Abstract
6. Li, L., Krantz, I.D., Deng, Y., Genin, A., Banta, A.B., Collins, C.C., Qi, M., Trask, B.J., Kuo, W.L., Cochran, J., Costa, T., Pierpont, M.E., Rand, E.B., Piccoli, D.A., Hood, L. and Spinner, N.B. (1997) Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nature Genet., 16, 243-251. MEDLINE Abstract
7. Oda, T., Elkahloun, A.G., Pike, B.L., Okajima, K., Krantz, I.D., Genin, A., Piccoli, D.A., Meltzer, P.S., Spinner, N.B., Collins, F.S. and Chandrasekharappa, S.C. (1997) Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nature Genet., 16, 235-242. MEDLINE Abstract
8. Krantz, I.D., Piccoli, D.A. and Spinner, N.B. (1997) Alagille syndrome. J. Med. Genet., 34, 152-157. MEDLINE Abstract
9. Krantz, I.D., Colliton, R.P., Genin, A., Rand, E.B., Li, L., Piccoli, D.A. and Spinner, N.B. (1998) Spectrum and frequency of Jagged1 (JAG1) mutations in Alagille syndrome patients and their families. Am. J. Hum. Genet., 62, 1361-1369. MEDLINE Abstract
10. Yuan, Z.-R., Kohsaka, T., Ikegaya, T., Suzuki, T., Okano, S., Abe, J., Kobayashi, N. and Yamada, M. (1998) Mutational analysis of the Jagged1 gene in Alagille syndrome families. Hum. Mol. Genet., 7, 1363-1369. MEDLINE Abstract
13. Mitsiadis, T.A., Henrique, D., Thesleff, I. and Lendahl, U. (1997) Mouse Serrate-1 (Jagged1): expression in the developing tooth is regulated by epithelial-mesenchymal interactions and fibroblast growth factor-4. Development, 124, 1473-1483. MEDLINE Abstract
14. Myat, A., Henrique, D., Ish-Horowicz, D. and Lewis, J. (1996) A chick homologue of Serrate and its relationship with Notch and Delta homologues during central neurogenesis. Dev. Biol., 174, 233-247. MEDLINE Abstract
15. Vargesson, N., Patel, K., Lewis, J. and Tickle, C. (1998) Expression patterns of Notch1, Serrate1, Serrate2 and Delta1 in tissues of the developing chick limb. Mech. Dev., 77, 197-200. MEDLINE Abstract
16. Swiatek, P.J., Lindsell, C.E., Franco del Amo, F., Weinmaster, G. and Gridley, T. (1994) Notch1 is essential for postimplantation development in mice. Genes Dev., 8, 707-719. MEDLINE Abstract
17. Conlon, R.A., Reaume, A.G. and Rossant, J. (1995) Notch1 is required for the coordinate segmentation of somites. Development, 121, 1533-1545. MEDLINE Abstract
18. Hrabé de Angelis, M., McIntyre, J. and Gossler, A. (1997) Maintenance of somite borders in mice requires the Delta homologue Dll1. Nature, 386, 717-721. MEDLINE Abstract
19. Kusumi, K., Sun, E., Kerrebrock, A.W., Bronson, R.T., Chi, D.-C., Bulotsky, M.S., Spencer, J.B., Birren, B.W., Frankel, W.N. and Lander, E.S. (1998) The mouse pudgy mutation disrupts Delta homologue Dll3 and initiation of early somite boundaries. Nature Genet., 19, 274-278. MEDLINE Abstract
20. Evrard, Y.A., Lun, Y., Aulehla, A., Gan, L. and Johnson, R.L. (1998) Lunatic fringe is an essential mediator of somite segmentation and patterning. Nature, 394, 377-381. MEDLINE Abstract
21. Zhang, N. and Gridley, T. (1998) Defects in somite formation in Lunatic fringe deficient mice. Nature, 394, 374-377. MEDLINE Abstract
22. Cohen, B., Bashirullah, A., Dagnino, L., Campbell, C., Fisher, W.W., Leow, C.C., Whiting, E., Ryan, D., Zinyk, D., Boulianne, G., Hui, C.-C., Gallie, B., Phillips, R.A., Lipshitz, H.D. and Egan, S.E. (1997) Fringe boundaries coincide with Notch-dependent patterning centres in mammals and alter Notch-dependent development in Drosophila. Nature Genet., 16, 283-288. MEDLINE Abstract
23. Bettenhausen, B., Hrabé de Angelis, M., Simon, D., Guenet, J.-L. and Gossler, A. (1995) Transient and restricted expression during mouse embryogenesis of Dll1, a murine gene closely related to DrosophilaDelta. Development, 121, 2407-2418. MEDLINE Abstract
24. Dunwoodie, S.L., Henrique, D., Harrison, S.M. and Beddington, R.S. (1997) Mouse Dll3: a novel divergent Delta gene which may complement the function of other Delta homologues during early pattern formation in the mouse embryo. Development, 124, 3065-3076. MEDLINE Abstract
25. Neidhardt, L.M., Kispert, A. and Herrmann, B.G. (1997) A mouse gene of the paired-related homeobox class expressed in the caudal somite compartment and in the developing vertebral column, kidney and nervous system. Dev. Genes Evol., 207, 330-339.
26. Hess, E.J., Collins, K.A., Copeland, N.G., Jenkins, N.A. and Wilson, M.C. (1994) Deletion map of the coloboma (Cm) locus on mouse Chromosome 2. Genomics, 21, 257-261. MEDLINE Abstract
27. Hess, E.J., Collins, K.A. and Wilson, M.C. (1996) Mouse model of hyperkinesis implicates SNAP-25 in behavioral regulation. J. Neurosci., 16, 3104-3111. MEDLINE Abstract
28. Theiler, K. and Varnum, D.S. (1981) Development of coloboma (Cm/+), a mutation with anterior lens adhesion. Anat. Embryol., 162, 121-126.
29. Hanahan, D. (1997) Signaling vascular morphogenesis and maintenance. Science, 277, 48-50. MEDLINE Abstract
30. Risau, W. (1997) Mechanisms of angiogenesis. Nature, 386, 671-674. MEDLINE Abstract
31. Zimrin, A.B., Pepper, M.S., McMahon, G.A., Nguyen, F., Montesano, R. and Maciag, T. (1996) An antisense oligonucleotide to the notch ligand jagged enhances fibroblast growth factor-induced angiogenesis in vitro. J. Biol. Chem., 271, 32499-32502. MEDLINE Abstract
32. Johnston, S.H., Rauskolb, C., Wilson, R., Prabhakaran, B., Irvine, K.D. and Vogt, T.F. (1997) A family of mammalian Fringe genes implicated in boundary determination and the Notch pathway. Development, 124, 2245-2254. MEDLINE Abstract
33. Jiang, R., Lan, Y., Chapman, H.D., Shawber, C., Norton, C.R., Serreze, D.V., Weinmaster, G. and Gridley, T. (1998) Defects in limb, craniofacial and thymic development in Jagged2 mutant mice. Genes Dev., 12, 1046-1057. MEDLINE Abstract
34. Muller, H.J. (1932) Further studies on the nature and causes of gene mutations. In Proceedings of the 6th International Congress on Genetics. Vol. 1, pp. 213-255.
35. Lindsell, C.E., Boulter, J., diSibio, G., Gossler, A. and Weinmaster, G. (1996) Expression patterns of Jagged, Delta1, Notch1, Notch2 and Notch3 genes identify ligand-receptor pairs that may function in neural development. Mol. Cell. Neurosci., 8, 14-27. MEDLINE Abstract
36. Bao, Z.Z. and Cepko, C.L. (1997) The expression and function of Notch pathway genes in the developing rat eye. J. Neurosci., 17, 1425-1434. MEDLINE Abstract
37. Artavanis-Tsakonas, S., Delidakis, C. and Fehon, R.G. (1991) The Notch locus and the cell biology of neuroblast segregation. Annu. Rev. Cell Biol., 7, 427-452. MEDLINE Abstract
38. Spinner, N.B. and Emanuel, B.S. (1996) Deletions and other structural abnormalities of the autosomes. In Rimoin, D.L., Connor, J.M. and Pyeritz, R.E. (eds), Emery and Rimoin's Principles and Practice of Medical Genetics, 3rd Edn. Churchill Livingstone, New York, NY, pp. 999-1025.
39. Soriano, P., Montgomery, C., Geske, R. and Bradley, A. (1991) Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell, 64, 693-702. MEDLINE Abstract
40. Mansour, S.L., Thomas, K.R. and Capecchi, M.R. (1988) Disruption of the proto-oncogene int-2 in mouse embryo-derived stem cells: a general strategy for targeting mutations to non-selectable genes. Nature, 336, 348-352. MEDLINE Abstract
41. Swiatek, P. and Gridley, T. (1993) Perinatal lethality and defects in hindbrain development in mice homozygous for a targeted mutation of the zinc finger gene Krox20. Genes Dev., 7, 2071-2084. MEDLINE Abstract
42. Gao, X., Copeland, N.G., Gilbert, D.J., Jenkins, N.A. and Gridley, T. (1998) Assignment of the murine Notch2 and Notch3 genes to chromosomes 3 and 17. Genomics, 49, 160-161. MEDLINE Abstract
43. Rowe, L.B., Nadeau, J.H., Turner, R., Frankel, W.N., Letts, V.A., Eppig, J.T., Ko, M.S., Thurston, S.J. and Birkenmeier, E.H. (1994) Maps from two interspecific backcross DNA panels available as a community genetic mapping resource. Mamm. Genome, 5, 253-274. MEDLINE Abstract
Q. ZhuGe, M. Zhong, W. Zheng, G.-Y. Yang, X. Mao, L. Xie, G. Chen, Y. Chen, M. T. Lawton, W. L. Young, et al. Notch-1 signalling is activated in brain arteriovenous malformations in humans
Brain,
October 7, 2009;
(2009)
awp246v1.
[Abstract][Full Text][PDF]
A. Nakao, H. Kajiya, H. Fukushima, A. Fukushima, H. Anan, S. Ozeki, and K. Okabe PTHrP Induces Notch Signaling in Periodontal Ligament Cells
Journal of Dental Research,
June 1, 2009;
88(6):
551 - 556.
[Abstract][Full Text][PDF]
I. Sorensen, R. H. Adams, and A. Gossler DLL1-mediated Notch activation regulates endothelial identity in mouse fetal arteries
Blood,
May 28, 2009;
113(22):
5680 - 5688.
[Abstract][Full Text][PDF]
J. S. Guseh, S. A. Bores, B. Z. Stanger, Q. Zhou, W. J. Anderson, D. A. Melton, and J. Rajagopal Notch signaling promotes airway mucous metaplasia and inhibits alveolar development
Development,
May 15, 2009;
136(10):
1751 - 1759.
[Abstract][Full Text][PDF]
T. Dai Notch Signaling and Cancer
Am. Assoc. Cancer Res. Educ. Book,
April 18, 2009;
2009(1):
71 - 79.
[Full Text][PDF]
V. Rodilla, A. Villanueva, A. Obrador-Hevia, A. Robert-Moreno, V. Fernandez-Majada, A. Grilli, N. Lopez-Bigas, N. Bellora, M. M. Alba, F. Torres, et al. Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer
PNAS,
April 14, 2009;
106(15):
6315 - 6320.
[Abstract][Full Text][PDF]
S. Yamanda, S. Ebihara, M. Asada, T. Okazaki, K. Niu, T. Ebihara, A. Koyanagi, N. Yamaguchi, H. Yagita, and H. Arai Role of ephrinB2 in nonproductive angiogenesis induced by Delta-like 4 blockade
Blood,
April 9, 2009;
113(15):
3631 - 3639.
[Abstract][Full Text][PDF]
D. Morrow, S. Guha, C. Sweeney, Y. Birney, T. Walshe, C. O'Brien, D. Walls, E. M. Redmond, and P. A. Cahill Notch and Vascular Smooth Muscle Cell Phenotype
Circ. Res.,
December 5, 2008;
103(12):
1370 - 1382.
[Abstract][Full Text][PDF]
M. Duarte, V. Kolev, D. Kacer, C. Mouta-Bellum, R. Soldi, I. Graziani, A. Kirov, R. Friesel, L. Liaw, D. Small, et al. Novel Cross-Talk between Three Cardiovascular Regulators: Thrombin Cleavage Fragment of Jagged1 Induces Fibroblast Growth Factor 1 Expression and Release
Mol. Biol. Cell,
November 1, 2008;
19(11):
4863 - 4874.
[Abstract][Full Text][PDF]
P.-N. Tsao, F. Chen, K. I. Izvolsky, J. Walker, M. A. Kukuruzinska, J. Lu, and W. V. Cardoso {gamma}-Secretase Activation of Notch Signaling Regulates the Balance of Proximal and Distal Fates in Progenitor Cells of the Developing Lung
J. Biol. Chem.,
October 24, 2008;
283(43):
29532 - 29544.
[Abstract][Full Text][PDF]
J. Aitsebaomo, A. L. Portbury, J. C. Schisler, and C. Patterson Brothers and Sisters: Molecular Insights Into Arterial-Venous Heterogeneity
Circ. Res.,
October 24, 2008;
103(9):
929 - 939.
[Abstract][Full Text][PDF]
H. Fukushima, A. Nakao, F. Okamoto, M. Shin, H. Kajiya, S. Sakano, A. Bigas, E. Jimi, and K. Okabe The Association of Notch2 and NF-{kappa}B Accelerates RANKL-Induced Osteoclastogenesis
Mol. Cell. Biol.,
October 15, 2008;
28(20):
6402 - 6412.
[Abstract][Full Text][PDF]
S. Urs, A. Roudabush, C. F. O'Neill, I. Pinz, I. Prudovsky, D. Kacer, Y. Tang, L. Liaw, and D. Small Soluble Forms of the Notch Ligands Delta1 and Jagged1 Promote in Vivo Tumorigenicity in NIH3T3 Fibroblasts with Distinct Phenotypes
Am. J. Pathol.,
September 1, 2008;
173(3):
865 - 878.
[Abstract][Full Text][PDF]
D. A. Venkatesh, K.-S. Park, A. Harrington, L. Miceli-Libby, J. K. Yoon, and L. Liaw Cardiovascular and Hematopoietic Defects Associated With Notch1 Activation in Embryonic Tie2-Expressing Populations
Circ. Res.,
August 15, 2008;
103(4):
423 - 431.
[Abstract][Full Text][PDF]
M.-J. Yoon, B.-K. Koo, R. Song, H.-W. Jeong, J. Shin, Y.-W. Kim, Y.-Y. Kong, and P.-G. Suh Mind bomb-1 Is Essential for Intraembryonic Hematopoiesis in the Aortic Endothelium and the Subaortic Patches
Mol. Cell. Biol.,
August 1, 2008;
28(15):
4794 - 4804.
[Abstract][Full Text][PDF]
L. Zhou, L. W. Li, Q. Yan, B. Petryniak, Y. Man, C. Su, J. Shim, S. Chervin, and J. B. Lowe Notch-dependent control of myelopoiesis is regulated by fucosylation
Blood,
July 15, 2008;
112(2):
308 - 319.
[Abstract][Full Text][PDF]
S.-M. Kwon, M. Eguchi, M. Wada, Y. Iwami, K. Hozumi, H. Iwaguro, H. Masuda, A. Kawamoto, and T. Asahara Specific Jagged-1 Signal From Bone Marrow Microenvironment Is Required for Endothelial Progenitor Cell Development for Neovascularization
Circulation,
July 8, 2008;
118(2):
157 - 165.
[Abstract][Full Text][PDF]
K. Niessen and A. Karsan Notch Signaling in Cardiac Development
Circ. Res.,
May 23, 2008;
102(10):
1169 - 1181.
[Abstract][Full Text][PDF]
R. C. A. Sainson, D. A. Johnston, H. C. Chu, M. T. Holderfield, M. N. Nakatsu, S. P. Crampton, J. Davis, E. Conn, and C. C. W. Hughes TNF primes endothelial cells for angiogenic sprouting by inducing a tip cell phenotype
Blood,
May 15, 2008;
111(10):
4997 - 5007.
[Abstract][Full Text][PDF]
G.-R. Dou, Y.-C. Wang, X.-B. Hu, L.-H. Hou, C.-M. Wang, J.-F. Xu, Y.-S. Wang, Y.-M. Liang, L.-B. Yao, A.-G. Yang, et al. RBP-J, the transcription factor downstream of Notch receptors, is essential for the maintenance of vascular homeostasis in adult mice
FASEB J,
May 1, 2008;
22(5):
1606 - 1617.
[Abstract][Full Text][PDF]
M. T. Holderfield and C. C.W. Hughes Crosstalk Between Vascular Endothelial Growth Factor, Notch, and Transforming Growth Factor-{beta} in Vascular Morphogenesis
Circ. Res.,
March 28, 2008;
102(6):
637 - 652.
[Abstract][Full Text][PDF]
F. A. High, M. M. Lu, W. S. Pear, K. M. Loomes, K. H. Kaestner, and J. A. Epstein Endothelial expression of the Notch ligand Jagged1 is required for vascular smooth muscle development
PNAS,
February 12, 2008;
105(6):
1955 - 1959.
[Abstract][Full Text][PDF]
H. Ogino, M. Fisher, and R. M. Grainger Convergence of a head-field selector Otx2 and Notch signaling: a mechanism for lens specification
Development,
January 15, 2008;
135(2):
249 - 258.
[Abstract][Full Text][PDF]
J. Jia, M. Lin, L. Zhang, J. P. York, and P. Zhang The Notch Signaling Pathway Controls the Size of the Ocular Lens by Directly Suppressing p57Kip2 Expression
Mol. Cell. Biol.,
October 15, 2007;
27(20):
7236 - 7247.
[Abstract][Full Text][PDF]
C. Roca and R. H. Adams Regulation of vascular morphogenesis by Notch signaling
Genes & Dev.,
October 15, 2007;
21(20):
2511 - 2524.
[Abstract][Full Text][PDF]
S. Pascoal and I. Palmeirim Watch-ing out for chick limb development
Integr. Comp. Biol.,
September 1, 2007;
47(3):
382 - 389.
[Abstract][Full Text][PDF]
A. E. Kiernan, R. Li, N. L. Hawes, G. A. Churchill, and T. Gridley Genetic Background Modifies Inner Ear and Eye Phenotypes of Jag1 Heterozygous Mice
Genetics,
September 1, 2007;
177(1):
307 - 311.
[Abstract][Full Text][PDF]
T. Gridley Notch signaling in vascular development and physiology
Development,
August 1, 2007;
134(15):
2709 - 2718.
[Abstract][Full Text][PDF]
K. Niessen and A. Karsan Notch signaling in the developing cardiovascular system
Am J Physiol Cell Physiol,
July 1, 2007;
293(1):
C1 - C11.
[Abstract][Full Text][PDF]
N. J. Gaspar, L. Li, A. M. Kapoun, S. Medicherla, M. Reddy, G. Li, G. O'Young, D. Quon, M. Henson, D. L. Damm, et al. Inhibition of Transforming Growth Factor beta Signaling Reduces Pancreatic Adenocarcinoma Growth and Invasiveness
Mol. Pharmacol.,
July 1, 2007;
72(1):
152 - 161.
[Abstract][Full Text][PDF]
M. K. Taylor, K. Yeager, and S. J. Morrison Physiological Notch signaling promotes gliogenesis in the developing peripheral and central nervous systems
Development,
July 1, 2007;
134(13):
2435 - 2447.
[Abstract][Full Text][PDF]
J. J. Hofmann and M. L. Iruela-Arispe Notch Signaling in Blood Vessels: Who Is Talking to Whom About What?
Circ. Res.,
June 8, 2007;
100(11):
1556 - 1568.
[Abstract][Full Text][PDF]
V. Bolos, J. Grego-Bessa, and J. L. de la Pompa Notch Signaling in Development and Cancer
Endocr. Rev.,
May 1, 2007;
28(3):
339 - 363.
[Abstract][Full Text][PDF]
S. Suchting, C. Freitas, F. le Noble, R. Benedito, C. Breant, A. Duarte, and A. Eichmann The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching
PNAS,
February 27, 2007;
104(9):
3225 - 3230.
[Abstract][Full Text][PDF]
I. B. Lobov, R. A. Renard, N. Papadopoulos, N. W. Gale, G. Thurston, G. D. Yancopoulos, and S. J. Wiegand Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting
PNAS,
February 27, 2007;
104(9):
3219 - 3224.
[Abstract][Full Text][PDF]
L. T. Raetzman, B. S. Wheeler, S. A. Ross, P. Q. Thomas, and S. A. Camper Persistent Expression of Notch2 Delays Gonadotrope Differentiation
Mol. Endocrinol.,
November 1, 2006;
20(11):
2898 - 2908.
[Abstract][Full Text][PDF]
K. D. Carroll, W. Bu, D. Palmeri, S. Spadavecchia, S. J. Lynch, S. A. E. Marras, S. Tyagi, and D. M. Lukac Kaposi's Sarcoma-Associated Herpesvirus Lytic Switch Protein Stimulates DNA Binding of RBP-Jk/CSL To Activate the Notch Pathway
J. Virol.,
October 1, 2006;
80(19):
9697 - 9709.
[Abstract][Full Text][PDF]
S. Cormier, S. Le Bras, C. Souilhol, S. Vandormael-Pournin, B. Durand, C. Babinet, P. Baldacci, and M. Cohen-Tannoudji The Murine Ortholog of Notchless, a Direct Regulator of the Notch Pathway in Drosophila melanogaster, Is Essential for Survival of Inner Cell Mass Cells.
Mol. Cell. Biol.,
May 1, 2006;
26(9):
3541 - 3549.
[Abstract][Full Text][PDF]
Z.-J. Liu, M. Xiao, K. Balint, A. Soma, C. C. Pinnix, A. J. Capobianco, O. C. Velazquez, and M. Herlyn Inhibition of endothelial cell proliferation by Notch1 signaling is mediated by repressing MAPK and PI3K/Akt pathways and requires MAML1
FASEB J,
May 1, 2006;
20(7):
1009 - 1011.
[Abstract][Full Text][PDF]
R. Brooker, K. Hozumi, and J. Lewis Notch ligands with contrasting functions: Jagged1 and Delta1 in the mouse inner ear
Development,
April 1, 2006;
133(7):
1277 - 1286.
[Abstract][Full Text][PDF]
G. G. Leblanc, J. F. Meschia, D. T. Stuss, and V. Hachinski Genetics of Vascular Cognitive Impairment: The Opportunity and the Challenges
Stroke,
January 1, 2006;
37(1):
248 - 255.
[Abstract][Full Text][PDF]
B.-K. Koo, H.-S. Lim, R. Song, M.-J. Yoon, K.-J. Yoon, J.-S. Moon, Y.-W. Kim, M.-c. Kwon, K.-W. Yoo, M.-P. Kong, et al. Mind bomb 1 is essential for generating functional Notch ligands to activate Notch
Development,
August 1, 2005;
132(15):
3459 - 3470.
[Abstract][Full Text][PDF]
T. R. Carlson, Y. Yan, X. Wu, M. T. Lam, G. L. Tang, L. J. Beverly, L. M. Messina, A. J. Capobianco, Z. Werb, and R. Wang Endothelial expression of constitutively active Notch4 elicits reversible arteriovenous malformations in adult mice
PNAS,
July 12, 2005;
102(28):
9884 - 9889.
[Abstract][Full Text][PDF]
B.-K. Koo, K.-J. Yoon, K.-W. Yoo, H.-S. Lim, R. Song, J.-H. So, C.-H. Kim, and Y.-Y. Kong Mind Bomb-2 Is an E3 Ligase for Notch Ligand
J. Biol. Chem.,
June 10, 2005;
280(23):
22335 - 22342.
[Abstract][Full Text][PDF]
L. C. Nehring, A. Miyamoto, P. W. Hein, G. Weinmaster, and J. M. Shipley The Extracellular Matrix Protein MAGP-2 Interacts with Jagged1 and Induces Its Shedding from the Cell Surface
J. Biol. Chem.,
May 27, 2005;
280(21):
20349 - 20355.
[Abstract][Full Text][PDF]
L. Chen and Q. Al-Awqati Segmental expression of Notch and Hairy genes in nephrogenesis
Am J Physiol Renal Physiol,
May 1, 2005;
288(5):
F939 - F952.
[Abstract][Full Text][PDF]
M. Nobta, T. Tsukazaki, Y. Shibata, C. Xin, T. Moriishi, S. Sakano, H. Shindo, and A. Yamaguchi Critical Regulation of Bone Morphogenetic Protein-induced Osteoblastic Differentiation by Delta1/Jagged1-activated Notch1 Signaling
J. Biol. Chem.,
April 22, 2005;
280(16):
15842 - 15848.
[Abstract][Full Text][PDF]
B. W. Purow, R. M. Haque, M. W. Noel, Q. Su, M. J. Burdick, J. Lee, T. Sundaresan, S. Pastorino, J. K. Park, I. Mikolaenko, et al. Expression of Notch-1 and Its Ligands, Delta-Like-1 and Jagged-1, Is Critical for Glioma Cell Survival and Proliferation
Cancer Res.,
March 15, 2005;
65(6):
2353 - 2363.
[Abstract][Full Text][PDF]
S. J. C. Mancini, N. Mantei, A. Dumortier, U. Suter, H. R. MacDonald, and F. Radtke Jagged1-dependent Notch signaling is dispensable for hematopoietic stem cell self-renewal and differentiation
Blood,
March 15, 2005;
105(6):
2340 - 2342.
[Abstract][Full Text][PDF]
A. Proweller, W. S. Pear, and M. S. Parmacek Notch Signaling Represses Myocardin-induced Smooth Muscle Cell Differentiation
J. Biol. Chem.,
March 11, 2005;
280(10):
8994 - 9004.
[Abstract][Full Text][PDF]
K. L. Hahn, J. Johnson, B. J. Beres, S. Howard, and J. Wilson-Rawls Lunatic fringe null female mice are infertile due to defects in meiotic maturation
Development,
February 15, 2005;
132(4):
817 - 828.
[Abstract][Full Text][PDF]
C Y Gregory-Evans, M J Williams, S Halford, and K Gregory-Evans Ocular coloboma: a reassessment in the age of molecular neuroscience
J. Med. Genet.,
December 1, 2004;
41(12):
881 - 891.
[Abstract][Full Text][PDF]
K. Lorent, S.-Y. Yeo, T. Oda, S. Chandrasekharappa, A. Chitnis, R. P. Matthews, and M. Pack Inhibition of Jagged-mediated Notch signaling disrupts zebrafish biliary development and generates multi-organ defects compatible with an Alagille syndrome phenocopy
Development,
November 15, 2004;
131(22):
5753 - 5766.
[Abstract][Full Text][PDF]
V. Domenga, P. Fardoux, P. Lacombe, M. Monet, J. Maciazek, L. T. Krebs, B. Klonjkowski, E. Berrou, M. Mericskay, Z. Li, et al. Notch3 is required for arterial identity and maturation of vascular smooth muscle cells
Genes & Dev.,
November 15, 2004;
18(22):
2730 - 2735.
[Abstract][Full Text][PDF]
M. Noseda, L. Chang, G. McLean, J. E. Grim, B. E. Clurman, L. L. Smith, and A. Karsan Notch Activation Induces Endothelial Cell Cycle Arrest and Participates in Contact Inhibition: Role of p21Cip1 Repression
Mol. Cell. Biol.,
October 15, 2004;
24(20):
8813 - 8822.
[Abstract][Full Text][PDF]
L. T. Krebs, J. R. Shutter, K. Tanigaki, T. Honjo, K. L. Stark, and T. Gridley Haploinsufficient lethality and formation of arteriovenous malformations in Notch pathway mutants
Genes & Dev.,
October 15, 2004;
18(20):
2469 - 2473.
[Abstract][Full Text][PDF]
S. M. Vercauteren and H. J. Sutherland Constitutively active Notch4 promotes early human hematopoietic progenitor cell maintenance while inhibiting differentiation and causes lymphoid abnormalities in vivo
Blood,
October 15, 2004;
104(8):
2315 - 2322.
[Abstract][Full Text][PDF]
H. Kokubo, S. Miyagawa-Tomita, H. Tomimatsu, Y. Nakashima, M. Nakazawa, Y. Saga, and R. L. Johnson Targeted Disruption of hesr2 Results in Atrioventricular Valve Anomalies That Lead to Heart Dysfunction
Circ. Res.,
September 3, 2004;
95(5):
540 - 547.
[Abstract][Full Text][PDF]
N. Tanimizu and A. Miyajima Notch signaling controls hepatoblast differentiation by altering the expression of liver-enriched transcription factors
J. Cell Sci.,
July 1, 2004;
117(15):
3165 - 3174.
[Abstract][Full Text][PDF]
M. Noseda, G. McLean, K. Niessen, L. Chang, I. Pollet, R. Montpetit, R. Shahidi, K. Dorovini-Zis, L. Li, B. Beckstead, et al. Notch Activation Results in Phenotypic and Functional Changes Consistent With Endothelial-to-Mesenchymal Transformation
Circ. Res.,
April 16, 2004;
94(7):
910 - 917.
[Abstract][Full Text][PDF]
A. Fischer, N. Schumacher, M. Maier, M. Sendtner, and M. Gessler The Notch target genes Hey1 and Hey2 are required for embryonic vascular development
Genes & Dev.,
April 15, 2004;
18(8):
901 - 911.
[Abstract][Full Text][PDF]
R. Trifonova, D. Small, D. Kacer, D. Kovalenko, V. Kolev, A. Mandinova, R. Soldi, L. Liaw, I. Prudovsky, and T. Maciag The non-transmembrane form of Delta1 but not of jagged1 Induces normal migratory behavior accompanied by FGF receptor 1-dependent transformation
J. Biol. Chem.,
February 9, 2004;
(2004)
300564200.
[Abstract][PDF]
J. Chu and E. H. Bresnick Evidence That C Promoter-binding Factor 1 Binding Is Required for Notch-1-mediated Repression of Activator Protein-1
J. Biol. Chem.,
March 26, 2004;
279(13):
12337 - 12345.
[Abstract][Full Text][PDF]
B. M. Kamath, N. B. Spinner, K. M. Emerick, A. E. Chudley, C. Booth, D. A. Piccoli, and I. D. Krantz Vascular Anomalies in Alagille Syndrome: A Significant Cause of Morbidity and Mortality
Circulation,
March 23, 2004;
109(11):
1354 - 1358.
[Abstract][Full Text][PDF]
F. le Noble, D. Moyon, L. Pardanaud, L. Yuan, V. Djonov, R. Matthijsen, C. Breant, V. Fleury, and A. Eichmann Flow regulates arterial-venous differentiation in the chick embryo yolk sac
Development,
January 15, 2004;
131(2):
361 - 375.
[Abstract][Full Text][PDF]
A. Singh and K.-W. Choi Initial state of the Drosophila eye before dorsoventral specification is equivalent to ventral
Development,
December 22, 2003;
130(25):
6351 - 6360.
[Abstract][Full Text][PDF]
S. Shi and P. Stanley Protein O-fucosyltransferase 1 is an essential component of Notch signaling pathways
PNAS,
April 29, 2003;
100(9):
5234 - 5239.
[Abstract][Full Text][PDF]
D. Small, D. Kovalenko, R. Soldi, A. Mandinova, V. Kolev, R. Trifonova, C. Bagala, D. Kacer, C. Battelli, L. Liaw, et al. Notch Activation Suppresses Fibroblast Growth Factor-dependent Cellular Transformation
J. Biol. Chem.,
April 25, 2003;
278(18):
16405 - 16413.
[Abstract][Full Text][PDF]
T. Gridley Notch signaling and inherited disease syndromes
Hum. Mol. Genet.,
April 2, 2003;
12(90001):
R9 - 13.
[Abstract][Full Text][PDF]
A. Slavotinek and L. G. Biesecker Genetic modifiers in human development and malformation syndromes, including chaperone proteins
Hum. Mol. Genet.,
April 2, 2003;
12(90001):
R45 - 50.
[Abstract][Full Text][PDF]
T. Schroeder, S. T. Fraser, M. Ogawa, S. Nishikawa, C. Oka, G. W. Bornkamm, S.-I. Nishikawa, T. Honjo, and U. Just Recombination signal sequence-binding protein Jkappa alters mesodermal cell fate decisions by suppressing cardiomyogenesis
PNAS,
April 1, 2003;
100(7):
4018 - 4023.
[Abstract][Full Text][PDF]
T. Iso, Y. Hamamori, and L. Kedes Notch Signaling in Vascular Development
Arterioscler Thromb Vasc Biol,
April 1, 2003;
23(4):
543 - 553.
[Abstract][Full Text][PDF]
J. Zhu, K. Motejlek, D. Wang, K. Zang, A. Schmidt, and L. F. Reichardt {beta}8 integrins are required for vascular morphogenesis in mouse embryos
Development,
March 8, 2003;
129(12):
2891 - 2903.
[Abstract][Full Text][PDF]
B. McCright, J. Lozier, and T. Gridley A mouse model of Alagille syndrome: Notch2 as a genetic modifier of Jag1 haploinsufficiency
Development,
March 4, 2003;
129(4):
1075 - 1082.
[Abstract][Full Text][PDF]
T. Takahashi, K. Takahashi, P. L. St. John, P. A. Fleming, T. Tomemori, T. Watanabe, D. R. Abrahamson, C. J. Drake, T. Shirasawa, and T. O. Daniel A Mutant Receptor Tyrosine Phosphatase, CD148, Causes Defects in Vascular Development
Mol. Cell. Biol.,
March 1, 2003;
23(5):
1817 - 1831.
[Abstract][Full Text][PDF]
Z.-J. Liu, T. Shirakawa, Y. Li, A. Soma, M. Oka, G. P. Dotto, R. M. Fairman, O. C. Velazquez, and M. Herlyn Regulation of Notch1 and Dll4 by Vascular Endothelial Growth Factor in Arterial Endothelial Cells: Implications for Modulating Arteriogenesis and Angiogenesis
Mol. Cell. Biol.,
January 1, 2003;
23(1):
14 - 25.
[Abstract][Full Text]
J. Morrissey, G. Guo, K. Moridaira, M. Fitzgerald, R. McCracken, T. Tolley, and S. Klahr Transforming Growth Factor-{beta} Induces Renal Epithelial Jagged-1 Expression in Fibrotic Disease
J. Am. Soc. Nephrol.,
June 1, 2002;
13(6):
1499 - 1508.
[Abstract][Full Text][PDF]
S. S. Nijjar, L. Wallace, H. A. Crosby, S. G. Hubscher, and A. J. Strain Altered Notch Ligand Expression in Human Liver Disease : Further Evidence for a Role of the Notch Signaling Pathway in Hepatic Neovascularization and Biliary Ductular Defects
Am. J. Pathol.,
May 1, 2002;
160(5):
1695 - 1703.
[Abstract][Full Text][PDF]
K. G. Leong, X. Hu, L. Li, M. Noseda, B. Larrivee, C. Hull, L. Hood, F. Wong, and A. Karsan Activated Notch4 Inhibits Angiogenesis: Role of {beta}1-Integrin Activation
Mol. Cell. Biol.,
April 15, 2002;
22(8):
2830 - 2841.
[Abstract][Full Text][PDF]
S. L. Dunwoodie, M. Clements, D. B. Sparrow, X. Sa, R. A. Conlon, and R. S. P. Beddington Axial skeletal defects caused by mutation in the spondylocostal dysplasia/pudgy gene Dll3 are associated with disruption of the segmentation clock within the presomitic mesoderm
Development,
January 4, 2002;
129(7):
1795 - 1806.
[Abstract][Full Text][PDF]
B.M. WEINSTEIN and N.D. LAWSON Arteries, Veins, Notch, and VEGF
Cold Spring Harb Symp Quant Biol,
January 1, 2002;
67(0):
155 - 162.
[Abstract][PDF]
N. D. Lawson, N. Scheer, V. N. Pham, C.-H. Kim, A. B. Chitnis, J. A. Campos-Ortega, and B. M. Weinstein Notch signaling is required for arterial-venous differentiation during embryonic vascular development
Development,
October 1, 2001;
128(19):
3675 - 3683.
[Abstract][Full Text][PDF]
V. Lindner, C. Booth, I. Prudovsky, D. Small, T. Maciag, and L. Liaw Members of the Jagged/Notch Gene Families Are Expressed in Injured Arteries and Regulate Cell Phenotype via Alterations in Cell Matrix and Cell-Cell Interaction
Am. J. Pathol.,
September 1, 2001;
159(3):
875 - 883.
[Abstract][Full Text][PDF]
T. Gridley Notch signaling during vascular development
PNAS,
May 8, 2001;
98(10):
5377 - 5378.
[Full Text][PDF]
H. Uyttendaele, J. Ho, J. Rossant, and J. Kitajewski Vascular patterning defects associated with expression of activated Notch4 in embryonic endothelium
PNAS,
May 8, 2001;
98(10):
5643 - 5648.
[Abstract][Full Text][PDF]
A. E. Kiernan, N. Ahituv, H. Fuchs, R. Balling, K. B. Avraham, K. P. Steel, and M. H. de Angelis The Notch ligand Jagged1 is required for inner ear sensory development
PNAS,
March 16, 2001;
(2001)
71496998.
[Abstract][Full Text]
H. Tsai, R. E. Hardisty, C. Rhodes, A. E. Kiernan, P. Roby, Z. Tymowska-Lalanne, P. Mburu, S. Rastan, A. J. Hunter, S. D. M. Brown, et al. The mouse slalom mutant demonstrates a role for Jagged1 in neuroepithelial patterning in the organ of Corti
Hum. Mol. Genet.,
March 1, 2001;
10(5):
507 - 512.
[Abstract][Full Text][PDF]
E. M. Conway, D. Collen, and P. Carmeliet Molecular mechanisms of blood vessel growth
Cardiovasc Res,
February 16, 2001;
49(3):
507 - 521.
[Full Text][PDF]
B McCright, X Gao, L Shen, J Lozier, Y Lan, M Maguire, D Herzlinger, G Weinmaster, R Jiang, and T Gridley Defects in development of the kidney, heart and eye vasculature in mice homozygous for a hypomorphic Notch2 mutation
Development,
January 2, 2001;
128(4):
491 - 502.
[Abstract][PDF]
Z. A. Eldadah, A. Hamosh, N. J. Biery, R. A. Montgomery, M. Duke, R. Elkins, and H. C. Dietz Familial Tetralogy of Fallot caused by mutation in the jagged1 gene
Hum. Mol. Genet.,
January 1, 2001;
10(2):
163 - 169.
[Abstract][Full Text][PDF]
M. Mina Regulation of Mandibular Growth and Morphogenesis
Critical Reviews in Oral Biology & Medicine,
January 1, 2001;
12(4):
276 - 300.
[Abstract][Full Text][PDF]
K. Shimizu, S. Chiba, N. Hosoya, K. Kumano, T. Saito, M. Kurokawa, Y. Kanda, Y. Hamada, and H. Hirai Binding of Delta1, Jagged1, and Jagged2 to Notch2 Rapidly Induces Cleavage, Nuclear Translocation, and Hyperphosphorylation of Notch2
Mol. Cell. Biol.,
September 15, 2000;
20(18):
6913 - 6922.
[Abstract][Full Text]
D. A Cabezas, R. Slaugh, F. Abidi, J F. Arena, R. E Stevenson, C. E Schwartz, and H. A Lubs A new X linked mental retardation (XLMR) syndrome with short stature, small testes, muscle wasting, and tremor localises to Xq24-q25.
J. Med. Genet.,
September 1, 2000;
37(9):
663 - 668.
[Abstract][Full Text]
L. T. Krebs, Y. Xue, C. R. Norton, J. R. Shutter, M. Maguire, J. P. Sundberg, D. Gallahan, V. Closson, J. Kitajewski, R. Callahan, et al. Notch signaling is essential for vascular morphogenesis in mice
Genes & Dev.,
June 1, 2000;
14(11):
1343 - 1352.
[Abstract][Full Text]
G. F. Hoyne, I. Le Roux, M. Corsin-Jimenez, K. Tan, J. Dunne, L. M. G. Forsyth, M. J. Dallman, M. J. Owen, D. Ish-Horowicz, and J. R. Lamb Serrate1-induced Notch signalling regulates the decision between immunity and tolerance made by peripheral CD4+ T cells
Int. Immunol.,
February 1, 2000;
12(2):
177 - 185.
[Abstract][Full Text][PDF]
T. Maynard, Y Wakamatsu, and J. Weston Cell interactions within nascent neural crest cell populations transiently promote death of neurogenic precursors
Development,
January 11, 2000;
127(21):
4561 - 4572.
[Abstract][PDF]
A Zine, T. Van De Water, and F de Ribaupierre Notch signaling regulates the pattern of auditory hair cell differentiation in mammals
Development,
January 8, 2000;
127(15):
3373 - 3383.
[Abstract][PDF]
A. Parks, K. Klueg, J. Stout, and M. Muskavitch Ligand endocytosis drives receptor dissociation and activation in the Notch pathway
Development,
January 4, 2000;
127(7):
1373 - 1385.
[Abstract][PDF]
L. T. Lam, C. Ronchini, J. Norton, A. J. Capobianco, and E. H. Bresnick Suppression of Erythroid but Not Megakaryocytic Differentiation of Human K562 Erythroleukemic Cells by Notch-1
J. Biol. Chem.,
June 23, 2000;
275(26):
19676 - 19684.
[Abstract][Full Text][PDF]
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