Aortic Coartation and the Zebrafish Model of Developmental Biology

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TOP: Post gadolinium MRA of the thoracic aorta in a young child (left) and conventional spin echo T1 (right) show a tight area of narrowing of the thoracic aorta just past the left subclavian artery origin consistent with aortic stenosis. The preductal / transverse portion of the aortic arch also seems more narrow than expected and the patient is very young. This could be a "tubular" or infantile type coarctation of the aorta.

BOTTOM: A: Circulation of green fluorescent beads in a normal zebrafish embryo. B: Absence of trunk circulation due to gridlock mutation, which caused malformation of vessels near the heart, as indicated by arrow. C: Adult zebrafish. (Source: Mary Beth Gardiner. The Reporter. Vanderbilt University Medical Center February 08, 2002)

Zebrafish, Danio rerio, are popular small fish kept in home aquariums. In recent years they have also become a mainstay of developmental biologists. The zebrafish is ideal for study of development of the circulatory system. Zebrafish are easy and comparatively inexpensive to maintain, rapidly produce large numbers of offspring, and have easily studied genetics. Like human beings, zebrafish are vertebrates, and follow the typical vertebrate path of embryonic development. The embryos are clear and develop outside of the mother’s body, allowing scientists to watch a zebrafish embryo grow into a newly formed fish under a microscope. This transparency makes observation of anatomical defects caused by genetic mutation easier. Moreover, zebrafish are particularly useful for studies of cardiovascular defects since survival of the embryos is not dependent on circulating blood flow. At 24 hours of development, the beating zebrafish heart is clearly visible. The entire circulatory system can be visualized using micro angiogram technique, injecting fluorescent micro beads.

Two genes, notch and gridlock (grl), interact in a single pathway that determines whether precursor cells are destined to become arteries or veins. The gridlock gene is expressed in the lateral plate mesoderm prior to vessel formation. Notch gene activation amplifies the expression of gridlock, causing precursor cells to develop into arterial vessels. Notch suppression reduced gridlock expression, causing aortic disruption. In the embryos with the mutation, there is a gap at the juncture of the two arterial vessels that come together to form the aorta. Injection of the micro beads demonstrates blockage at this point and no distal blood flow. This defect is restricted to arterial vessels, venous branches are not affected. This was the first molecular evidence that defined the endothelial cells in arteries as being different from the endothelial cells in veins in the early stages of development. The gridlock gene is present in every organism studied, from the fruit fly to human. The protein encoded by the gridlock gene in zebrafish shares 86 percent of its structure with its human’s analog. Interesting note: Recent medical and surgical reviews make little mention of any underlying genetic basis for human coarctation and seem to favor a physiologic / hemodynamic cause for the stenosis. This doesn't make much sense for a congenital abnormality and I suspect it is due to a lack of familiarity with recent findings in Danio rerio.

Source:

Mary Beth Gardiner. The Reporter. Vanderbilt University Medical Center February 08, 2002

Tao P. Zhong, Sarah Childes, James P. Leu, Mark C. Fishman. The Gridlock Siganaling Pathway Fashions the First Embryonic Artery. Nature(414), 216-220, 2001