Biomedical Engineering Reference
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ceruloplasmin (a liver-specific multicopper oxidase gene), can be visualized at this
time asymmetrically on the left-hand side of the endoderm up to 32hpf. Together
with other pan-endodermal markers such as foxA1, foxA2, and foxA3 (Odenthal and
Nusslein-Volhard, 1998) and prox1 (Glasgow and Tomarev, 1998; Ho et al., 1999)
and hhex, two established liver markers in amniotes (Oliver et al., 1993; Keng
et al., 1998; Sosa-Pineda et al., 2000), these cells, derived from the primitive gut,
gradually form the liver. This has been investigated and characterized using a
transgenic line of zebrafish that expressed GFP in the gut (Field et al., 2003).
Hepatocyte aggregation between 24 and 28hpf first leads to a thickening in the
intestinal rod, followed by an outward projection to the left side and a looping of the
intestinal primordium. By 50hpf, liver tissue is easily recognized and a period of
significant growth begins. In addition, the tissue that eventually connects the liver to
the intestinal primordium becomes the polarized epithelium of the bile duct. Like
mammals, the zebrafish liver produces bile, which is stored in gall bladder (Pack
et al., 1996). Although there are other striking similarities to its mammalian
counterpart, there are exceptions. In particular, there are no true portal lobules in
the zebrafish liver.
During vascularization, endothelial cells labeled with Tie2-GFP have been
shown to partially encapsulate the liver bud and subsequently start to invade it
around 60hpf. The mechanisms by which this occurs have not been fully
investigated although the aryl hydrocarbon receptor nuclear translocator (ARNT),
a basic helix-loop-helix-PAS heterodimeric transcription factor commonly asso-
ciated with detoxification, may be involved along with other gene pathways (Hill
et al., 2009). This was noted as part of an initial characterization of the zebrafish
arnt2 null mutant in which, among various other abnormalities, dilated liver
sinusoids were found to merge abnormally to form an extensive, labyrinth-like
network of vascular channels. Previous mouse models have also implicated AHR
and ARNT as well as other dimerization partners such as hif-1
in the normal
development of the murine vasculature and liver (Walisser et al., 2004a, 2004b),
but further investigation is required. By 72hpf, vascularization is essentially
complete and the liver becomes perfused with blood shortly after (Pack et al., 1996;
Isogai et al., 2001).
Embryogenesis is essentially complete by this time and the digestive system is
fully functional. Even though the zebrafish embryo can survive purely on a reserve
of yolk during the first 4-5 days of development, it is ready to begin feeding.
Development of a physiologically functional liver is therefore very rapid in
comparison to other vertebrate models. With the exception of minor differences,
the general anatomy, organization, cellular composition, and function of a healthy
adult zebrafish liver are virtually the same as in mammals (Hinton and Couch, 1998),
and the early embryonic stages of hepatogenesis are similar to that of mice
(Duncan, 2003; Field et al., 2003; Ober et al., 2003). Likewise, with regard to
disease phenotypes, the histopathology of cholestasis, fatty liver (steatosis), and
neoplasia is also comparable (Spitsbergen et al., 2000; Amatruda et al., 2002; Amali
et al., 2006).
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