The secretory pathway calcium ATPase PMR-1/SPCA1 has essential roles in cell migration during Caenorhabditis elegans embryonic development

Maintaining levels of calcium in the cytosol is important for many cellular events, including cell migration, where localized regions of high calcium are required to regulate cytoskeletal dynamics, contractility, and adhesion. Studies show inositol-trisphosphate receptors (IP3R) and ryanodine receptors (RyR), which release calcium into the cytosol, are important regulators of cell migration. Similarly, proteins that return calcium to secretory stores are likely to be important for cell migration. The secretory protein calcium ATPase (SPCA) is a Golgi-localized protein that transports calcium from the cytosol into secretory stores. SPCA has established roles in protein processing, metal homeostasis, and inositol-trisphosphate signaling. Defects in the human SPCA1/ATP2C1 gene cause Hailey-Hailey disease (MIM# 169600), a genodermatosis characterized by cutaneous blisters and fissures as well as keratinocyte cell adhesion defects. We have determined that PMR-1, the Caenorhabditis elegans ortholog of SPCA1, plays an essential role in embryogenesis. Pmr-1 strains isolated from genetic screens show terminal phenotypes, such as ventral and anterior enclosure failures, body morphogenesis defects, and an unattached pharynx, which are caused by earlier defects during gastrulation. In Pmr-1 embryos, migration rates are significantly reduced for cells moving along the embryo surface, such as ventral neuroblasts, C-derived, and anterior-most blastomeres. Gene interaction experiments show changing the activity of itr-1/IP3R and unc-68/RyR modulates levels of embryonic lethality in Pmr-1 strains, indicating pmr-1 acts with these calcium channels to regulate cell migration. This analysis reveals novel genes involved in C. elegans cell migration, as well as a new role in cell migration for the highly conserved SPCA gene family.
Author Summary During growth or regeneration after damage, skin cells migrate from basal to superficial layers, forming tight attachments that protect an individual from environmental assaults. Proteins that remove calcium from the cell cytosol into secretory stores, where it is available for future release, play a key role in skin cell integrity. Defects in these secretory pathway calcium ATPase (SPCA) channels in humans cause Hailey-Hailey disease, a chronic disorder marked by skin lesions in areas of high-stress. Our study of the SPCA gene pmr-1 in Caenorhabditis elegans indicates the gene is essential for viability. Embryos with defective PMR-1 die with cell attachment defects superficially similar to those of Hailey-Hailey disease patients. To better understand this phenotype, we tracked the position of individual cells during development of pmr-1 mutant embryos. This analysis revealed that the cell attachment defects are caused by primary failures in cell migration. We also identified other calcium channel proteins involved in this process, indicating proper regulation of calcium is crucial for cell migration in C. elegans. If SPCA proteins act similarly in humans, this research will lead to better understanding of the molecules important for skin cell regeneration, as well as help to explain the defects observed in Hailey-Hailey disease patients.