NDK-1, the Homolog of NM23-H1/H2 Regulates Cell Migration and Apoptotic Engulfment in C. elegans

Abstract

Abnormal regulation of cell migration and altered rearrangement of cytoskeleton are characteristic of metastatic cells. The first described suppressor of metastatic processes is NM23-H1, which displays NDPK (nucleoside-diphosphate kinase) activity. To better understand the role of nm23 genes in cell migration, we investigated the function of NDK-1, the sole Caenorhabditis elegans homolog of group I NDPKs in distal tip cell (DTC) migration. Dorsal phase of DTC migration is regulated by integrin mediated signaling. We find that ndk-1 loss of function mutants show defects in this phase. Epistasis analysis using mutants of the α-integrin ina-1 and the downstream functioning motility-promoting signaling module (referred to as CED-10 pathway) placed NDK-1 downstream of CED-10/Rac. As DTC migration and engulfment of apoptotic corpses are analogous processes, both partially regulated by the CED-10 pathway, we investigated defects of apoptosis in ndk-1 mutants. Embryos and germ cells defective for NDK-1 showed an accumulation of apoptotic cell corpses. Furthermore, NDK-1::GFP is expressed in gonadal sheath cells, specialized cells for engulfment and clearence of apoptotic corpses in germ line, which indicates a role for NDK-1 in apoptotic corpse removal. In addition to the CED-10 pathway, engulfment in the worm is also mediated by the CED-1 pathway. abl-1/Abl and abi-1/Abi, which function in parallel to both CED-10/CED-1 pathways, also regulate engulfment and DTC migration. ndk-1(-);abi-1(-) double mutant embryos display an additive phenotype (e. g. enhanced number of apoptotic corpses) which suggests that ndk-1 acts in parallel to abi-1. Corpse number in ndk-1(-);ced-10(-) double mutants, however, is similar to ced-10(-) single mutants, suggesting that ndk-1 acts downstream of ced-10 during engulfment. In addition, NDK-1 shows a genetic interaction with DYN-1/dynamin, a downstream component of the CED-1 pathway. In summary, we propose that NDK-1/NDPK might represent a converging point of CED-10 and CED-1 pathways in the process of cytoskeleton rearrangement.

Nucleoside diphosphate kinases (NDPKs) in animal development

“…Moreover, NDK-1 interacts with the CED-1 pathway through DYN-1 in engulfment through DYN-1. Thus, this study is the first to link an NDPK to apoptotic engulfment [71] (Fig. 1c) and consistent with a large body of data confirming that NDPK and dynamin are ubiquitous functional partners across model systems.…”

“…Indeed, an increased number of apoptotic cell corpses were measured in the germline of ndk-1(RNAi) animals and in ndk-1(ok314) embryos, as compared to wild-type animals [71]. Furthermore, NDK-1 accumulation was detected in sheath cells around dying germ cell corpses (Fig.…”

“…Therefore, an epistasis analysis was performed with genes involved in integrinmediated signaling (members of the CED-10/Rac signaling pathway such as vab-3/Pax6, ina-1/alpha-integrin, unc-73/ Trio, mig-2/RhoG, ced-5/Dock180, ced-12/Elmo, ced-10/ Rac) and with abl-1/ABL and abi-1/ABI which have been shown to act in parallel to the CED-10 pathway [74]. Epistasis analysis revealed that NDK-1 functions downstream of CED-10/Rac and in parallel to ABI-1/ABI in DTC migration [71]. In multicellular organisms, unnecessary or dangerous cells are often eliminated by type I programmed cell death, apoptosis.…”

“…The development of their germ cells is arrested at the mitotic phase. In addition, gonad arms in these mutants display an abnormal shape [71]. Wild-type C. elegans hermaphrodites possess two U-shaped gonad arms whose morphogenesis is directed by specialized leader cells called distal tip cells (DTCs), which are located at the distal edges of either arm [72].…”

“…DTC migration provides a tractable system to monitor genes influencing guided cell migration [72]. In a transgenic strain expressing a translational fusion NDK-1 reporter, NDK-1 accumulation was detected in the DTCs [71]. Consistent with this NDK-1 expression profile, an incomplete DTC migration was observed in ndk-1 loss-of-function mutants; DTCs stopped their migration prematurely in the third (or dorsal) phase of migration, resulting in a ''J-shaped'' gonad arm [71] (Fig.…”