Fear-of-intimacy mediated zinc transport controls the function of Zn-finger transcription factors involved in myogenesis

Abstract

Zinc is a component of one-tenth of all human proteins. Its cellular concentration is tightly regulated because its dyshomeostasis has catastrophic health consequences. Two families of zinc transporters control zinc homeostasis in organisms, but there is little information about their specific developmental roles. We show that the ZIP transporter Fear-of-intimacy (Foi) is necessary for the formation of Drosophila muscles. In foi mutants, myoblasts segregate normally, but their specification is affected, leading to the formation of a misshapen muscle pattern and distorted midgut. The observed phenotypes could be ascribed to the inactivation of specific zincfinger transcription factors (ZFTFs), supporting the hypothesis that they are a consequence of intracellular depletion of zinc. Accordingly, foi phenotypes can be rescued by mesodermal expression of other ZIP members with similar subcellular localization. We propose that Foi acts mostly as a transporter to regulate zinc intracellular homeostasis, thereby impacting on the activity of ZFTFs that control specific developmental processes. Our results additionally suggest a possible explanation for the presence of large numbers of zinc transporters in organisms based on differences in ion transport specificity and/or degrees of activity among transporters.

Copper and Zinc Homeostasis: Lessons from Drosophila melanogaster

“…In the myoblast development, the expression of target genes of zinc-dependent transcription factors, such as Minc and Kruppel, was severely altered in foi mutants. In agreement, the phenotypes could be rescued by overexpression of other dZip genes with the same cellular localization such as dZip42C.1 and dZip71B (Carrasco-Rando et al, 2016 ). All these results support the role of foi as a Zn transporter and the impact of its loss-of-function in the activity of zinc-finger transcription factors.…”

“…FOI is not expressed in the gut, but is one of the cellular Zn importers in several other tissues (probably cooperating with dZip42C.1). The gene fear of intimacy ( foi ) showed up in genetic screens aiming to identify mutations affecting the development of fly gonads and trachea (van Doren, 2003 ; Mathews et al, 2005 ), embryonic nervous system (Pielage et al, 2004 ), and fly muscles (Carrasco-Rando et al, 2016 ). FOI is able to transport Zn in yeast and mammalian cells (Mathews et al, 2005 ).…”

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“…It may affect the normal patterns of children and adolescents growth 2 . Obesity among children and adolescents is continuing to rise and reach up to 18% of children and adolescents aged [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] in 2016 according to the World Health Organization (WHO) 3 . The aetiology of obesity is multimodal and multifactorial, which makes it difficult to identify causative and contributing factors 4 .…”

Drosophila melanogaster Models of Metal-Related Human Diseases and Metal Toxicity

“…Foi is also necessary for correct specification and consequent differentiation of mesodermal derivatives, acting as a Zn transporter that regulates Zn cellular homeostasis. Its function can be partially replaced by other Zn transporters of the same family that have a similar subcellular localization [ 118 ].…”