Model Organisms in Drug Discovery

186 GENETICS AND GENOMICS IN THE ZEBRAFISH
simple salt solution within a petri-dish. There is no shortage of embryos to
work with because a single pair of adult fish will spawn every week, producing
a few hundred embryos per mating. Embryos develop quickly and reach the
end of somatogenesis by 24 h post-fertilization. The heart starts to beat at 28 h
and the first blood cells can be seen rushing through the vasculature by 30 h.
At 72 h the intestine undergoes peristaltic movements and most cell types in
the visceral tract have differentiated (Schilling, 2002). By day 5 larvae start to
feed, whereas prior to that point they relied on their yolk supply.
Over the years it has become appreciated that the ease of manipulating
embryos and zebrafish larvae opens up the opportunity to study organogenesis
in ways not previously possible. Researchers have developed novel
methods to study their favorite fish organ systems and have developed genetic
screens that previously were considered to be impossible in vertebrate systems.
One impressive demonstration of the advantages of zebrafish in designing and
carrying out genetic screens was carried out in retinal axons. A screen was
designed where fixed larvae (5 days old) were mounted in agarose and two
different lipophilic dyes (DiI and DiO) were injected into distinct positions,
thereby labeling two separate populations of retinal ganglion axons within the
eye (Baier et al., 1996; Trowe et al., 1996). The dyes travel along the
corresponding neurons until they reach the respective areas of the
contralateral optic tectum, outlining both the neuronal path from retina to
tectum and the retinotectal projection. The method was so reproducible and
scalable that it could be used as a basis for a genetic screen: overall processing
of one larva, including mounting, dye injection and analysis, took just 1 min,
and scoring 125 000 larvae resulted in the identification of 144 mutants in
approximately 35 genes that exhibited defects in their retinotectal projections.
Although this example is a particularly impressive one, it merely highlights
the versatility of zebrafish as a screening tool. Various laboratories are
involved in looking at processes as diverse as thrombosis (Jagadeeswaran and
Sheenan, 1999), angiogenesis (Weinstein et al., 1995; Habeck et al., 2002),
hematopoiesis (Thisse and Zon, 2002) and many other areas that require
studying recent medically relevant events. It is this versatility, combined with
genetics and methods to manipulate both embryos and larvae alike, that has
contributed to the success of zebrafish.
7.2 Pathway conservation between humans and fish: what
difference do 400 million years make?
A common ancestor between humans and zebrafish lived roughly 400 million
years ago, which at times has raised the question of whether the similarities
between the two species are outnumbered by the differences. This is a question
of particular relevance to those who use zebrafish as an entry point to learn