Zinc dysregulation inslc30a8(znt8) mutant zebrafish leads to blindness and disrupts bone mineralisation

Abstract

Zinc is an essential cofactor for many cellular processes including gene transcription, insulin secretion and retinal function. Excessive free Zn2+ is highly toxic and consequently intracellular zinc is tightly controlled by a system of transporters, metallothioneins (MTs) and storage vesicles. Here we describe the developmental consequences of a missense allele of zinc efflux transporter slc30a8 (znt8) in zebrafish. Homozygous slc30a8hu1798 larvae are virtually blind and develop very little or no bone mineral. We show that zinc is stored in pigmented cells (melanophores) of healthy larvae but in slc30a8hu1798 mutants it instead accumulates in the bone and brain. Supporting a role for pigment cells in zinc homeostasis, nacre zebrafish, which lack melanophores, also show disrupted zinc homeostasis. The photoreceptors of slc30a8hu1798 fish are severely depleted while those of nacre fish are enriched with zinc. We propose that developing zebrafish utilise pigmented cells as a zinc storage organ, and that Slc30a8 is required for transport of zinc into these cells and into photoreceptors.

Transcriptional Regulation and Protein Localization of Zip10, Zip13 and Zip14 Transporters of Freshwater Teleost Yellow Catfish Pelteobagrus fulvidraco Following Zn Exposure in a Heterologous HEK293T Model

“…Thus, intracellular free Zn 2+ must be maintained at a required reasonable level by various Zn transporters, buffering metallothioneins, and sequestering vesicles [ 5 ]. For example, in the zebrafish, Zip6 is required for zinc homeostasis maintenance in T-cell development [ 6 ] and pigmented cells store zinc and maintain zinc homeostasis through Znt8 [ 7 ]. In rainbow trout, MT and other zinc-binding proteins contribute to normal zinc homeostasis in liver cells [ 8 ].…”