Pigment Dilution Mutants from Fish Models with Connection to Lysosome-Related Organelles and Vesicular Traffic Genes

Abstract

An interesting question in developmental biology is why mutations in genes with functions essential for the majority of cells produce diseases affecting only specific tissues. For example, pigment dilution disorders are often the consequence of mutations in conserved vesicular traffic genes. In Hermansky-Pudlak, Griscelli, and Chediak-Higashi pigment dilution syndromes, vesicular traffic mutations affect several organs with one characteristic in common: to carry out their functions they depend to a great extent on lysosome-related organelles (LROs), such as the melanosomes in melanocytes. Conserved multimeric complexes, present in most cell types, target proteins to lysosomes or selected LROs using transport vesicles. By studying these diseases or the model organisms that are defective in these processes, we have learned that every cell type possesses a unique way to regulate its vesicular traffic machinery and to assemble its multimeric complexes. This is accomplished by subunits from these multimeric complexes acting in a cell-specific manner. Here, we review several fish pigment dilution mutants that represent models for human vesicular traffic diseases.

Mutations in vacuolar H+-ATPase subunits lead to biliary developmental defects in zebrafish

“…Cell layers within the eye were disrupted in pn (Figure 3G-H), with the most striking abnormalities in the retinal cell layer and the retinal pigmented epithelium. These findings are similar to previous descriptions of eye pigmentation mutants caused by mutations in genes encoding subunits of the V-H + -ATPase and vacuolar protein sorting (VPS) complexes (Navarro et al, 2008), complexes important in intracellular protein trafficking and degradation.…”

The genetic basis of divergent pigment patterns in juvenile threespine sticklebacks

“…Bloc1s3 is important in the packaging of pigment into organelles (Navarro et al , 2008), and disruption of Bloc1s3 leads to a dilute pigment phenotype in mice (Starcevic and Dell’Angelica, 2004). Mutations of Tyrosinase ( Tyr ), a key enzyme in melanin synthesis, eliminate all pigmentation in zebrafish and medaka (Koga et al , 1995; Page-McCaw et al , 2004).…”

snow white, a Zebrafish Model of Hermansky-Pudlak Syndrome Type 5

“…Following classic studies in mammalian melanocytes (Seiji et al 1963a,b), early ultrastructural studies of the goldfish eye produced data describing melanosome maturation (Turner et al 1975;Abramowitz et al 1977;Kajishima and Takeuchi 1977). Interestingly, while many components of this pathway appear to be conserved across vertebrates, it has been noted that fibrillar striations do not develop in fish; instead, ILVs appear to remain intact inside the developing melanosome, acting as a substrate for melanin deposition themselves ( Figure 7, B and C) (Navarro et al 2008).…”

“…Furthermore, the average circumference of snw melanosomes was significantly smaller than sibling melanosomes at all time points examined ( Figure 2H). Eumelanosomes (containing eumelanin) complete the process of maturation by elongating to adopt an ellipsoid morphology; in contrast, pheomelanosomes (containing pheomelanin) remain round (Hirose and Matsumoto 1994;Kim and Choi 1998;Nguyen et al 2002, Navarro et al 2008. Both round and ellipsoid (red arrowheads) melanosomes were observed in the RPE of wild-type embryos, with a varying range of diameters (Figure 2, A, C, and E).…”