Conclusions

The lessons learned in the zebrafish are likely to be readily transferred to other vertebrate organisms, including mammals, since the complex circulatory system of the zebrafish is in most respects quite similar to that of other vertebrates. A comparison between the blood vessels of zebrafish and other vertebrates presents a striking degree of anatomical and functional conservation of vascular pattern and anatomy, suggesting that vascular development is directed by genetically programmed, evolutionarily conserved control mechanisms. Indeed, it is clear from the analysis of a variety of zebrafish orthologs of vascular-specific genes first described in other species that most of these genes have very similar spatial and temporal expression patterns in the fish. Some of the genetic control mechanisms responsible for regulating the expression of these genes and for vascular differentiation and patterning have now begun to be studied in the zebrafish. The specific advances in our understanding of the A-V differentiation pathway will be important in designing methods for directing organ-specific vessel growth for tissue regeneration, and for targeting specific vessel components for inhibition of growth. It is anticipated that our knowledge and understanding in this area will only continue to grow with the zebrafish as an integral component, resulting in the identification of novel factors and the more subtle characterization of the various vessel types and their growth.

Glossary

Clone: An exact copy of biological material such as DNA, a whole cell, or a complete organism.

Diploid: A complete set of chromosomes, present in somatic (non-sex-determining) cells, consisting of two copies of each chromosome. Human beings have 46 chromosomes in their diploid cells.

Epistasis: The ability of a gene to mask the phenotypic effects of another gene. A downstream gene is epistatic to any upstream genes that produce the same effect.

Fate map: A map of an embryo showing areas that are destined to develop into specific adult tissues and organs.

Genetic linkage map: A linear map of the relative positions of genes along a chromosome. Gene distances are determined by the frequency at which two gene loci are separated during chromosomal recombination.

Germ-line: The propagation of genetic information from one generation to the next via the germ cell. Germ-line mutation is one that has occurred in a germ cell and will be passed to the next generation. Same logic pertains to the term germ-line transmission.

Gynogenotes: Individuals that derive their chromosome number solely from the maternal contribution, rather than half from each parent.

Haploid: A single set of chromosomes, present in the egg and sperm cells of animals. Humans have 23 chromosomes in their reproductive cells.

Homolog: One member of a chromosome pair, or a gene similar in structure and evolutionary origin to a gene in another species.

Morpholino oligonucleotides: Short, antisense sequences of DNA (oligos) with a morpholino backbone that provides stability, and an increased life span in vivo.

Ploidy: Refers to the number of single sets of chromosomes in a given cell or organism.

Recessive mutations: Mutations affecting those genes require two identical copies to be expressed.

References

1. Streisinger, G., Walker, C., Dower, N., Knauber, D., and Singer, F. (1981). Production of clones of homozygous diploid zebra fish (Brachydanio rerio). Nature 291, 293-296.

2. Nusslein-Volhard, C., and Wieschaus, E. (1980). Mutations affecting segment number and polarity in Drosophila. Nature 287, 795-801.

3. Kimmel, C. B., Warga, R. M., and Schilling, T. F. (1990). Origin and organization of the zebrafish fate map. Development 108, 581-594.

4. Westerfield, M. (2001). The Zebrafish Book, 4th ed. University of Oregon Press, Eugene, OR.

5. Stuart, G. W., McMurray, J. V., and Westerfield, M. (1988). Replication, integration and stable germ-line transmission of foreign sequences injected into early zebrafish embryos. Development 103, 403-412.

6. Schulte-Merker, S., van Eeden, F. J., Halpern, M. E., Kimmel, C. B., and Nusslein-Volhard, C. (1994). No tail (ntl) is the zebrafish homologue of the mouse T (Brachyury) gene. Development 120, 1009-1015.

7. Development (1996). Vol.123 [special issue].

8. Nasevicius, A., and Ekker, S. C. (2000). Effective targeted gene 'knockdown' in zebrafish. Nat. Genet. 26, 216-220.

9. Habeck, H., Odenthal, J., Walderich, B., Maischein, H., and Schulte-Merker, S. (2002). Analysis of a zebrafish VEGF receptor mutant reveals specific disruption of angiogenesis. Curr. Biol. 12, 1405-1412.

10. Lawson, N. D., and Weinstein, B. M. (2002). In vivo imaging of embryonic vascular development using transgenic zebrafish. Dev. Biol. 248, 307-318.

11. Isogai, S., Lawson, N. D., Torrealday, S., Horiguchi, M., and Weinstein, B. M. (2003). Angiogenic network formation in the developing vertebrate trunk. Development 130, 5281-5290.

12. Huang, C. C., Lawson, N. D., Weinstein, B. M., and Johnson, S. L. (2003). reg6 is required for branching morphogenesis during blood vessel regeneration in zebrafish caudal fins. Dev. Biol. 264, 263-274.

13. Wang, H. U., Chen, Z. F., and Anderson, D. J. (1998). Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell 93, 741-753.

14. 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.

15. 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.

16. Zhong, T. P., Rosenberg, M., Mohideen, M. A., Weinstein, B., and Fishman, M. C. (2000). Gridlock, an HLH gene required for assembly of the aorta in zebrafish. Science 287, 1820-1824.

17. Lawson, N. D., Mugford, J. W., Diamond, B. A., and Weinstein, B. M. (2003). Phospholipase C gamma-1 is required downstream of vascular endothelial growth factor during arterial development. Genes Dev. 17, 1346-1351.

18. Pola, R., Ling, L. E., Silver, M., Corbley, M. J., Kearney, M., Blake Pepinsky, R., Shapiro, R., Taylor, F. R., Baker, D. P., Asahara, T., and Isner, J. M. (2001). The morphogen Sonic hedgehog is an indirect angiogenic agent upregulating two families of angiogenic growth factors. Nat. Med. 7, 706-711.

19. Mukouyama, Y. S., Shin, D., Britsch, S., Taniguchi, M., and Anderson, D. J. (2002). Sensory nerves determine the pattern of arterial differentiation and blood vessel branching in the skin. Cell 109, 693-705.

20. Visconti, R. P., Richardson, C. D., and Sato, T. N. (2002). Orchestration of angiogenesis and arteriovenous contribution by angiopoietins and vascular endothelial growth factor (VEGF). Proc. Natl. Acad. Sci. USA 99, 8219-24.

21. Springer, M. L., Ozawa, C. R., Banfi, A., Kraft, P. E., Ip, T. K., Brazelton, T. R., and Blau, H. M. (2003). Localized arteriole formation directly adjacent to the site of VEGF-Induced angiogenesis in muscle. Mol. Ther. 7, 441-449.

Further Reading

Grunwald, D. J., and Eisen, J. S. (2002). Headwaters of the zebrafish— emergence of a new model vertebrate. Nat. Rev. Genet. 3, 717-724.

Isogai, S., Horiguchi, M., and Weinstein, B. M. (2001). The vascular anatomy of the developing zebrafish: an atlas of embryonic and early larval development. Dev. Biol. 230, 278-301.

Isogai, S., Lawson, N. D., Torrealday, S., Horiguchi, M., and Weinstein, B. M. (2003). Angiogenic network formation in the developing vertebrate trunk. Development 130, 5281-5290. This reference exemplifies one of the key attributes of the zebrafish, the ability to image the developing embryo, and how this attribute translates to an increased understanding of microvascular development and formation.

Kimmel, C. B., Warga, R. M., and Schilling, T. F. (1990). Origin and organization of the zebrafish fate map. Development 108, 581-594.

Lawson, N. D., and Weinstein, B. M. (2002a). Arteries and veins: making a difference with zebrafish. Nat. Rev. Genet. 3, 674-682. This paper reviews of much of the literature detailing our knowledge of blood vessel differentiation and how the zebrafish as a model has contributed to this knowledge.

Lawson, N. D., and Weinstein, B. M. (2002b). In vivo imaging of embryonic vascular development using transgenic zebrafish. Dev. Biol. 248, 307-318.

Nasevicius, A., and Ekker, S. C. (2000). Effective targeted gene "knockdown" in zebrafish. Nat. Genet. 26, 216-220.

Rasooly, R. S., Henken, D., Freeman, N., Tompkins, L., Badman, D., Briggs, J., and Hewitt, A. T. (2003). Genetic and genomic tools for zebrafish research: the NIH zebrafish initiative. Dev. Dyn. 228, 490-496.

Schulte-Merker, S., van Eeden, F. J., Halpern, M. E., Kimmel, C. B., and Nusslein-Volhard, C. (1994). No tail (ntl) is the zebrafish homologue of the mouse T (Brachyury) gene. Development 120, 1009-1015. Stainier, D. Y., Fouquet, B., Chen, J. N., Warren, K. S., Weinstein, B. M., Meiler, S. E., Mohideen, M. A., Neuhauss, S. C., Solnica-Krezel, L., Schier, A. F., Zwartkruis, F., Stemple, D. L., Malicki, J., Driever, W., and Fishman, M. C. (1996). Mutations affecting the formation and function of the cardiovascular system in the zebrafish embryo. Development 123, 285-292. This paper describes many of the original mutations that were identified as affecting the vasculature of the zebrafish. Many of these mutations provided the foundation for current cardiovascular research in the zebrafish.

Capsule Biography

Brant M. Weinstein obtained his Ph.D. in 1992 from the Massachusetts Institute of Technology. He has headed the Unit on Vertebrate Organogenesis within the Laboratory of Molecular Genetics at the National Institute of Child Health and Human Development (NICHD) since 1997. His laboratory, supported by the intramural program of the NICHD, studies vascular development using the zebrafish.

Kameha Kidd received her doctorate at the University of Arizona in 2002 under the tutelage of Drs. Stuart K. Williams and James B. Hoying. She is currently a postdoctoral fellow, under the direction of Dr. Brant Weinstein, at the National Institute of Child Health and Human Development at the NIH. Her research interest is in microvascular development and organogenesis for application in therapeutic angiogenesis and tissue engineering.

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