Function and regulation of copper in mammalian tissue differentiation

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PROJECT SUMMARY/ABSTRACT Mammalian tissue development requires a series of tightly regulated and dynamic fluctuations in metabolic pathways, growth factor signaling, gene expression, and cofactor availability. An important cofactor is copper (Cu), an essential but toxic trace nutrient that is required for oxidative phosphorylation, removal of reactive oxygen species, iron homeostasis, and pro-survival signaling pathways. Cu is important for normal tissue development, and we and others have shown that Cu is required for differentiation of skeletal muscle and neuronal cells. This need for Cu is highlighted by the severe postnatal developmental impairment in cases of Cu deficiency including profound hypotonia and neurodegeneration. Menkes is a fatal genetic Cu deficiency disease caused by mutations in ATP7A, which encodes a trans-Golgi Cu transporting ATPase. Several open questions remain about the critical Cu targets during tissue differentiation and how regulated gene expression contributes to prioritized Cu distribution to those targets. These questions create a gap in knowledge of Cu handling that limit the development of therapies to treat Cu diseases including Menkes. Our preliminary data indicate that ATP7A is required for skeletal muscle cell differentiation and that Cu and ATP7A may contribute to regulated inhibition of TGF- signaling pathways that prevent differentiation. We also discovered that post- transcriptional regulation of the Atp7a RNA contributes to differentiation-dependent tuning of ATP7A expression. The proposed research program includes two projects to understand prioritization of Cu during skeletal muscle differentiation by first focusing on function and regulation of ATP7A. The first project will study the role of Cu and ATP7A in modulating TGF- signaling to promote differentiation in vitro and in vivo. The second will focus on uncovering the mechanisms of post-transcriptional regulation of Atp7a RNA and how they control ATP7A expression. These projects will identify new signaling pathways regulated by Cu and new mechanisms of Cu regulation. This work will open the possibility of modulating Cu availability by targeting post-transcriptional regulatory pathways and raise the possibility of controlling TGF- signaling by manipulating Cu availability to treat Cu-related and developmental disease.