The Caenorhabditis elegans homolog of human copper chaperone Atox1, CUC-1, aids in distal tip cell migration

Xiaolu Zhang,Stéphanie Blockhuys,Marc Pilon,Pernilla Wittung-Stafshede,Ranjan Devkota

doi:10.1007/s10534-020-00239-z

Xiaolu Zhang, Stéphanie Blockhuys + Show 3 more

Open Access

https://doi.org/10.1007/s10534-020-00239-z

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Abstract

Cell migration is a fundamental biological process involved in for example embryonic development, immune system and wound healing. Cell migration is also a key step in cancer metastasis and the human copper chaperone Atox1 was recently found to facilitate this process in breast cancer cells. To explore the role of the copper chaperone in other cell migration processes, we here investigated the putative involvement of an Atox1 homolog in Caenorhabditis elegans, CUC-1, in distal tip cell migration, which is a key process during the development of the C. elegans gonad. Using knock-out worms, in which the cuc-1 gene was removed by CRISPR-Cas9 technology, we probed life span, brood size, as well as distal tip cell migration in the absence or presence of supplemented copper. Upon scoring of gonads, we found that cuc-1 knock-out, but not wild-type, worms exhibited distal tip cell migration defects in approximately 10–15% of animals and, had a significantly reduced brood size. Importantly, the distal tip cell migration defect was rescued by a wild-type cuc-1 transgene provided to cuc-1 knock-out worms. The results obtained here for C. elegans CUC-1 imply that Atox1 homologs, in addition to their well-known cytoplasmic copper transport, may contribute to developmental cell migration processes.

Highlights

Copper (Cu) is an essential nutrient in living organisms acting as a cofactor in proteins facilitating for example respiration, iron transport, oxidative stress protection, peptide hormone production, pigmentation, and blood clotting (Puig and Thiele 2002; Matson Dzebo et al 2016)
We recently showed that Atox1 facilitates breast cancer cell migration (Blockhuys et al 2020) and, upon analyzing breast cancer patient tumor data, high Atox1 levels in the tumors correlated with worse prognosis of patient survival (Blockhuys et al 2020)
We found that almost 10% of cuc-1 mutants had distal tip cells (DTCs) migration defects (Fig. 4 d,e), whereas no such defects were observed in wild-type worms

Summary

Introduction

Copper (Cu) is an essential nutrient in living organisms acting as a cofactor in proteins facilitating for example respiration, iron transport, oxidative stress protection, peptide hormone production, pigmentation, and blood clotting (Puig and Thiele 2002; Matson Dzebo et al 2016). In order to avoid toxicity of free Cu ions, intracellular Cu is regulated by devoted Cu transport proteins that assist uptake, efflux, and distribution of the metal ion to load Cu-dependent proteins (Festa and Thiele 2011; Matson Dzebo et al 2016). After copper transporter protein 1 (Ctr1)-mediated uptake, the cytoplasmic Cu chaperone Atox transports Cu to ATP7A and ATP7B in the trans-Golgi network (Puig and Thiele 2002). The Atox1ATP7A/B Cu transport pathway is conserved in many organisms, including bacteria, yeast and (of importance for this study) the round-worm Caenorhabditis elegans (C. elegans) (Klomp et al 1997; Wakabayashi et al 1998, Puig and Thiele 2002)

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