The Secretory Pathway Calcium ATPase PMR-1/SPCA1 Has Essential Roles in Cell Migration during Caenorhabditis elegans Embryonic Development

Abstract

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.

Glycosyl Phosphatidylinositol Anchor Biosynthesis Is Essential for Maintaining Epithelial Integrity during Caenorhabditis elegans Embryogenesis

“…The pigv-1 ( qm34 ) was retrieved from an EMS screening conducted by Hekimi et al [ 25 ]. For analysis using GFP fusions, F2 progeny exhibiting pigv-1 phenotypes and carrying the markers were selected from crosses between pigv-1 ( qm34 ) and the following strains: SU93 jcIs1[ajm-1 :: gfp , unc-29(+) , rol-6p :: rol-6(su1006)] [ 46 ], SU265 jcIs17[hmp-1p :: hmp-1 :: gfp , dlg-1p :: dlg-1 :: dsRed , rol-6p :: rol-6(su1006)] [ 47 ], SU467 pIs7[pha-4p :: pm :: gfp , rol-6p :: rol-6(su1006)] [ 48 ], FT17 xnIs3[par-6p :: par-6 :: gfp , unc-119(+)] ; unc-119(ed3) III , MOT63 temIs59[pIC26 :: pkc-3] ; unc-119(ed3) III , WS4918 opIS310[ced-1p :: yfp :: act-5 :: let-858 3'UTR , unc-119(+)] [ 49 ], VJ402 fgEx1[erm-1p :: erm-1 :: gfp , rol-6p :: rol-6(su1006)] [ 33 ], ML1735 mcIs50[lin-26p :: vab-10(actin-binding domain) :: gfp , myo-2p :: GFP] [ 50 ], plag-2p :: piga-1 :: egfp -expressing strain was generated by Murata et al [ 10 ].…”

The Role of Ca2+ Signaling in Aging and Neurodegeneration: Insights from Caenorhabditis elegans Models

“…Double mutants of pmr-1 and a gain of function mutant of itr-1 (the worm IP 3 R orthologue) reduced lethality, and double mutants of pmr-1 and a loss-of-function mutant of itr-1 showed enhanced lethality or were not viable. In contrast, depletion with RNAi of unc-68 (the worm orthologue of RyR) considerably increased the viability of pmr-1 mutants [92]. Although difficult to explain, these findings strongly suggest that Ca 2+ signaling play a critical role in cell migration and attachment during embryogenesis.…”

“…PMR1 also has an important role in embryogenesis [92], and pmr-1 mutants show important defects in cell migration and attachment that resemble the loss of skin cell adhesion observed in Hailey-Hailey disease, a dominant human disease caused by the loss of one of the copies of the SPCA1 gene [93]. Interestingly, the level of embryonic lethality could be modulated by changing the activity of IP 3 R and RyR channels, although the modulation of each of these channels produced opposite effects.…”

Correlation between cell migration and reactive oxygen species under electric field stimulation

“…Collective cell migration is an important cellular event, which is involved in many different physiological processes such as embryonic development, [1][2][3] tissue repair, [4][5][6] angiogenesis, [7][8][9] and wound healing. [10][11][12] In particular, it has been suggested that this collective behavior plays important roles in the invasion and spread of malignant cells.…”