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RESEARCH COMMUNICATION
1 CIISA, Faculdade de Medicina Veterinária, 1300-0-477 Lisboa, Portugal; 2 Instituto de Medicina Molecular, Faculdade de Medicina, 1649-9-028 Lisboa, Portugal; 3 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G1X5; 4 Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8
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Abstract |
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[Keywords: Angiogenesis; Dll4; Notch; haploinsufficiency; dosage sensitivity; arteriogenesis]
Received July 12, 2004; revised version accepted August 19, 2004.
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Results and Discussion |
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TopAbstractResults and DiscussionMaterials and methodsAcknowledgmentsReferences |
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). In zebrafish, Notch signaling is required for arterial identity by suppressing the venous fate in developing artery cells (Zhong et al. 2001; Lawson et al. 2002). In mice, the Notch4 receptor (Villa et al. 2001) and the Delta-like 4 (Dll4) ligand (Shutter et al. 2000; Mailhos et al. 2001; Villa et al. 2001) are specifically expressed in arterial and not venous endothelial cells, suggesting a possible similar role. Knockout of the Notch4 receptor gave no obvious phenotype alone, although Notch1/Notch4 double mutant embryos did show severe vascular remodeling defects (Krebs et al. 2000), which were also observed, to a lesser degree, in Hey1/Hey2 double mutants, the putative downstream targets of Notch signaling (Fischer et al. 2004). Here we show, in contrast, that the Dll4 ligand alone is required in a dosage-sensitive manner for normal arterial patterning in development.
The Dll4 gene was inactivated by targeted disruption in embryonic stem (ES) cells. The targeting vector was designed to replace the initiation codon and the first three coding exons with the 
-galactosidase (lacZ) reporter gene (Fig. 1A). Electroporation of R1 ES cells with the targeting vector followed by G418 selection resulted in the derivation of four correctly gene-targeted ES cell lines. Chimeric mice were generated by aggregation between Dll4+/- ES cells and ICR host embryos. When crossed with wild-type ICR females, five male chimeras produced F1 agouti pups at 100% frequency. Genotyping of F1 agouti mice by Southern blotting or polymerase chain reaction (PCR; Fig. 1B,C) identified Dll4+/- individuals at only 21% frequency (55 out of 260), suggesting the death in utero of a proportion of the Dll4+/- F1 embryos. Outcrossing these viable heterozygotes to ICR mice still resulted in a reduced number of heterozygotes in subsequent generations. This effect was dependent on the genetic background, as no live Dll4+/- offspring were obtained when the 100% germ-line transmitter chimeric males were crossed with 129/Sv-CP females (n = 65).
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The Dll4+/- embryos were dissected at embryonic day 7.5-10.5 (E7.5-E10.5) and stained with X-gal or immunostained for PECAM. In pre-somite stages, lacZ expression was exclusively detected in trophoblast giant cells (data not shown). Around the two-somite stage (E8.0), the lacZ reporter was expressed in the cardiac crescent and the primordia of the dorsal aortae (Fig. 2A). At the five- to 10-somite stage (E8.5), it was expressed in the heart, paired dorsal aortae, branchial arch arteries, internal carotid arteries, umbilical artery, vitelline artery, and in the posterior region of the yolk sac where the arteries are formed (Fig. 2B,C). This expression pattern is consistent with previous reports that Dll4 is an early marker for arterial endothelial cells (Shutter et al. 2000; Mailhos et al. 2001; Villa et al. 2001).
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Defects in vascular structures were also seen within the Dll4+/- embryos, most notably the reduction of the caliber of the dorsal aortae. At E9.0 the dorsal aortae were already thinner than normal in 60% of the embryos (n = 15), a feature which was accentuated at E9.5 (n = 32) and E10.5 (n = 34). The constriction of the dorsal aortae was primarily observed rostrally between the cardiac level and the intersections with the branchial arch arteries (Fig. 2K-P), but some embryos exhibited longer zones of constriction extending caudally (data not shown). At both E9.5 and E10.5 (n = 66), 90% of the embryos displayed some degree of aortic constriction. The degree of constriction was variable among embryos and also between the dorsal aortae of any specific embryo. Interestingly, when the aortic lesions were asymmetric (observed in 50% of the embryos), the left dorsal aorta was always more severely affected. The potential impact of these arterial defects on the development of the venous system was also investigated. Reduced caliber and disorganization of the anterior and posterior cardinal veins were observed in the Dll4+/- embryos, but only in those cases where the dorsal aortae were severely affected, suggesting that the venous defect is a secondary response to a primary arterial restriction (Fig. 2, cf. L,O and M,P).
Surviving Dll4+/- mice were apparently normal, suggesting that in these animals the major defects caused by reduction of Dll4 are transient. Subtle defects in the ability of the adult mice to undertake neoangiogenesis have not yet been examined. However, both the male and female mice are fertile, showing that the neovascularization associated with gametogenesis and pregnancy is not impaired. This allowed us to intercross Dll4+/- mice to examine the homozygous null phenotype. The embryos were collected at E8.5-E10.5, genotyped by PCR of yolk sac DNA, and analyzed by X-gal staining and PECAM immunostaining. Homozygous mutant embryos were found at normal Mendelian frequencies at E9.5 (wild-type, 27.1%; Dll4+/-, 47.9%; Dll4-/-, 25.0%; n = 239) but at E10.5 no viable Dll4-/- embryos were found (n = 48). In addition, no Dll4-/- offspring was obtained (wild-type, 62.5%; Dll4+/-, 37.5%; n = 39). As expected, RT-PCR analysis demonstrated the complete absence of Dll4 mRNA in the null embryos (Fig. 1D).
The Dll4-/- embryos showed more severe and precocious vascular defects than heterozygotes. Mutant embryos were morphologically normal until E8.5 (data not shown), and LacZ expression from the Dll4 locus was similar in intensity to the heterozygotes. The correct migration and aggregation of the angioblasts occurred to form the dorsal aortae, showing no disruption of the onset of vasculogenesis. However, the dorsal aortae already showed a clear reduction in diameter by E8.75 (Fig. 3A,B). By E9.0 the homozygous null embryos were highly delayed and abnormal, with severe pericardial swelling, and drastically reduced dorsal aortic diameter in the anterior region (Fig. 3E-H). Not only were the major arteries abnormal; branching morphogenesis was also affected. Dll4-/- embryos showed an abnormal accumulation of lacZ+ endothelial cells in the apical portion of the intersomitic vessels and an abnormally dilated dorsal vessel in this region (Fig. 3, cf. G and H).This defect would result in abnormal blood circulation in the embryo, with misdirection from the dorsal aorta to the lateral vessels.
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By E9.5 these phenotypic traits were accentuated, with more pronounced growth retardation and arterial atrophy, the dorsal aortae being absent or reduced to a rudimentary capillary plexus (Fig. 3I,J). The hearts in these embryos showed reduced atrial and ventricular chambers, and the ventricular trabeculation was markedly reduced (data not shown). The head vasculature consisted of a simple plexus of disorganized and fused vessels (Fig. 3J). Venous development was also impaired in the null embryos. At E8.75 the anterior cardinal vein already appeared to have a reduced caliber and ectopic branching at some points, and the sinus venosus appeared smaller (Fig. 3A,B). By E9.0 the anterior cardinal vein was further reduced, and by E9.5, a distinct anterior cardinal vein was absent and the embryos showed a very reduced sinus venosus (Fig. 3I,J). Therefore, although the major arteries and veins of the embryo form in the absence of Dll4, their later development is severely disrupted. As Dll4 expression is artery-specific, the venous defects are likely secondary to arterial patterning and growth problems.
In zebrafish, Notch signaling has been implicated in the specification of arterial endothelial cells by suppressing the venous cell fate (Lawson et al. 2001, 2002; Zhong et al. 2001). To investigate whether the disruption of vascular development in Dll4 mutants could be at least partially attributable to abnormal identity of the vascular endothelial cells, we carried out RNA in situ hybridization and immunostaining to determine the expression of arterial and venous markers. In Dll4-/- embryos with residual intact dorsal aortae, the VEGF receptor, Flk1, was normally expressed in both arteries and veins, and the Dll4-lacZreporter was expressed in the arteries. However none of the downstream arterial markers studied (EphrinB2, Connexin37, and Connexin40) were expressed in the endothelium (Fig. 4A-F; data not shown). This is consistent with the proposed pathway from zebrafish, where VEGF signaling upstream of Notch signaling promotes arterial cell fate (Lawson et al. 2002). In addition to loss of arterial markers, the venous marker EphB4 was ectopically expressed in the dorsal aortae as well as the cardinal veins (Fig. 4J). In some null embryos, from E9.0, the dorsal aorta fused with the anterior cardinal vein at the level of the sinus venosus (Fig. 4J), consistent with possible loss of separate identity of the two vessels. These data strongly suggest an involvement of the Notch signaling pathway, mediated through the Dll4 ligand in a cell-autonomous manner, in the establishment of the endothelial arterial cell phenotype in mice. The similarity of the Dll4-/- phenotype to that of the Notch1/4 double mutants (Krebs et al. 2000) is consistent with this, as is the contrasting effect of endothelialspecific activated Notch expression (Uyttendaele et al. 2001). Loss of arterial vascular identity, in Dll4-/- mutants, in turn, could cause angiogenic defects leading to a generalized disruption of the vasculature and embryonic death. However, this loss of arterial endothelial identity is probably not sufficient to explain all the vascular defects observed, such as reduction in aortic caliber and complete absence of arterial organization in the yolk sac. Notch signaling, in addition to regulating the endothelial cell fate, may also regulate the growth of arteries, through the regulation of endothelial cell proliferation and/or the maintenance of a pool of undifferentiated angioblasts.
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; Ferrara et al. 1996), which lies upstream of Notch signaling in arterial development (Lawson et al. 2002). This suggests that the development and patterning of the arterial system may be controlled by levels of availability of critical ligands. Interestingly, both VEGF and Dll4 have been shown to be up-regulated by hypoxia (Shweiki et al. 1992; Mailhos et al. 2001), which is one of the environmental factors that can impinge on vascular patterning and growth. Presumably, exquisite sensitivity to ligand levels helps to ensure appropriate vascular responses to changing external environments. Sensitivity of the embryonic vasculature to Dll4 levels raises the possibility that Dll4 might be a good target for intervention in adult neovascularization. |
Materials and methods |
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TopAbstractResults and DiscussionMaterials and methodsAcknowledgmentsReferences |
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Mouse Dll4 genomic clones were isolated from a 129/Sv genomic library and characterized using standard protocols. In the targeting vector, a 2.0-kilobase (kb) DNA fragment encompassing the start codon and the first three exons of the Dll4-coding sequence was deleted and substituted by a lacZ and PGK-neo cassette, flanked by 1.5-kb 5'and 5-kb 3' homologous regions (Fig. 1A). This vector was linearized with NotI and electroporated into R1 ES cells. Correctly targeted clones were identified by PCR assays and confirmed by Southern blotting (Fig. 1B). Chimeric mice were generated by morula aggregation (Nagy et al. 1993), and males were crossed with ICR females.
Screening for germ-line transmission and genotyping was performed by PCR analysis of tail biopsy DNA (Fig. 1C) using the following primers: P1, 5'-GGGGAATCAGCTTTTCAGGAA-3'; P2, 5'-CGAACTCCTG CAGCCGCAGCT-3'; P3, 5'-ACGACGTTGTAATACGAC-3' (Fig. 1A).
Generation of Dll4+/- ES-derived embryos
Dll4-/- ES cell lines were used in aggregations with EGFP-expressing tetraploid embryos as described (Hadjantonakis et al. 1998). Two-cell diploid embryos were fused to become tetraploid one-cell embryos, cultured to the four-cell stage, and aggregated with ES cells. Composite embryos were cultured overnight and then transferred to pseudopregnant recipients.
In situ hybridization, immunohistochemistry, and lacZ staining
Embryonic age was initially determined by the date of the formation of the copulation plug and confirmed by number of somites. Whole-mount immunohistochemistry and lacZ staining were carried out by standard techniques (Hogan et al. 1994). Antibodies were from Pharmingen (PECAM) and R&D Systems (EphB4). Digoxigenin-labeled RNA probes were transcribed from linearized templates, and in situ hybridization of cryosections was carried out as described (Henrique et al. 1997). Probe sizes were as follows: EphrinB2, 700 bp; Flk1, 800 bp; Connexin37, 978 bp; Connexin40, 1000 bp.
RT-PCR analysis
Individual yolk sacs and embryos from Dll4+/- intercrosses were dissected and used to isolate total RNA from which first-strand cDNA was synthesized using a SuperScript Preamplification System kit (GIBCOBRL). First-strand cDNA (0.1 µg) was used for PCR with specific primers for Dll4 (forward, 5'-AGCTGGAAGTGGACTGTGGT-3'; reverse, 5'-TAGAGTCCCTGGGAGAGCAA-3') and, as a control, -actin (forward, 5'-ACCGTGAAAAGATGACCCAG-3'; reverse, 5'-GCTGTGGTGGT GAAGCTGTA-3'). PCR products were visualized by ethidium bromide staining (Fig. 1D).
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Acknowledgments |
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TopAbstractResults and DiscussionMaterials and methodsAcknowledgmentsReferences |
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Footnotes |
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5 These authors contributed equally to this work. 
6 Present address: Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-0-8582, Japan.
7 Corresponding author. E-MAIL: rossant{at}mshri.on.ca; FAX (416) 586-8588.
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References |
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TopAbstractResults and DiscussionMaterials and methodsAcknowledgmentsReferences |
|---|
Ferrara, N., Carver-Moore, K., Chen, H., Dowd, M., Lu, L., O'Shea, K.S., Powell-Braxton, L., Hillan, K.J., and Moore, M.W. 1996. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380: 439-442.[CrossRef][Medline]
Fischer, A., Schumacher, N., Maier, M., Sendtner, M., and Gessler, M. 2004. The Notch target genes Hey1 and Hey2 are required for embryonic vascular development. Genes & Dev. 18: 901-911.
Hadjantonakis, A.K., Gertsenstein, M., Ikawa, M., Okabe, M., and Nagy, A. 1998. Generating green fluorescent mice by germline transmission of green fluorescent ES cells. Mech. Dev. 76: 79-90.[CrossRef][Medline]
Henrique, D., Hirsinger, E., Adam, J., LeRoux, I., Pourquie, O., Ish-Horowicz, D., and Lewis, J. 1997. Maintenance of neuroepithelial progenitor cells by Delta-Notch signalling in the embryonic chick retina. Curr. Biol. 13: 661-670.
Hogan, B., Beddington, R., Constantini, F., and Lacy, E. 1994. Manipulating the mouse embryo. A laboratory manual. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.
Krebs, L.T., Xue, Y., Norton, C.R., Shutter, J.R., Maguire, M., Sundberg, J.P., Gallahan, D., Closson, V., Kitajewski, J., Callahan, R., et al. 2000. Notch signaling is essential for vascular morphogenesis in mice. Genes & Dev. 14: 1343-1352.
Lawson, N.D., Scheer, N., Pham, V.N., Kim, C.H., Chitnis, A.B., Campos-Ortega, J.A., and Weinstein, B.M. 2001. Notch signaling is required for arterial-venous differentiation during embryonic vascular development. Development 128: 3675-3683.
Lawson, N.D., Vogel, A.M., and Weinstein, B.M. 2002. sonic hedgehog and vascular endothelial growth factor act upstream of the Notch pathway during arterial endothelial differentiation. Dev. Cell 3: 127-136.[CrossRef][Medline]
Mailhos, C., Modlich, U., Lewis, J., Harris, A., Bicknell, R., and Ish-Horowicz, D. 2001. Delta4, an endothelial specific notch ligand expressed at sites of physiological and tumor angiogenesis. Differentiation 69: 135-144.[CrossRef][Medline]
Nagy, A., Rossant, J., Nagy, R., Abramow-Newerly, W., and Roder, J.C. 1993. Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. Proc. Natl. Acad. Sci. 90: 8424-8428.
Shawber, C.J. and Kitajewski, J. 2004. Notch function in the vasculature: Insights from zebrafish, mouse and man. Bioessays 26: 225-234.[CrossRef][Medline]
Shutter, J.R., Scully, S., Fan, W., Richards, W.G., Kitajewski, J., Deblandre, G.A., Kintner, C.R., and Stark, K.L. 2000. Dll4, a novel Notch ligand expressed in arterial endothelium. Genes & Dev. 14: 1313-1318.
Shweiki, D., Itin, A., Soffer, D., and Keshet, E. 1992. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359: 843-845.[CrossRef][Medline]
Uyttendaele, H., Ho, J., Rossant, J., and Kitajewski, J. 2001. Vascular patterning defects associated with expression of activated Notch4 in embryonic endothelium. Proc. Natl. Acad. Sci. 98: 5643-5648.
Villa, N., Walker, L., Lindsell, C.E., Gasson, J., Iruela-Arispe, M.L., and Weinmaster, G. 2001. Vascular expression of Notch pathway receptors and ligands is restricted to arterial vessels. Mech. Dev. 108: 161-164.[CrossRef][Medline]
Zhong, T.P., Childs, S., Leu, J.P., and Fishman, M.C. 2001. Gridlock signalling pathway fashions the first embryonic artery. Nature 414: 216-220.[CrossRef][Medline]
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