Glucose 6-phosphate dehydrogenase deficiency enhances germ cell apoptosis and causes defective embryogenesis in Caenorhabditis elegans

Yang, H-C; Chen, T-L; Wu, Y-H; Cheng, K-P; Lin, Y-H; Cheng, M-L; Ho, H-Y; Lo, S J; Chiu, D T-Y

Despite MAPK pathway being not directly associated with egg production upon G6PD knockdown (Figures 6b-d) , loss of function of sek-1 or mek-1 exhibits a substantial increase of hatching in G6PD-knockdown C. elegans embryos (8.3-fold and 9.6-fold, respectively) ( Figure 7) . Since G6PD is a major NADPH producing enzyme in cells, we hypothesized that there is a yet identified molecular sensor that respond to NADPH status in C. elegans. Upon G6PD knockdown, such NADPH sensor modulates the downstream signaling required for normal hatching. Such notion is not unprecedented. The translocation of the transcription factor, Nrf2 (Nuclear factor erythroid 2p45-related transcription factor), is modulated by a NADPH-requiring enzyme, NADPH oxidase (NOX). 38 This exemplifies a positive regulation of signal transduction affected by NADPH. On the other hand, a recently identified NADPH sensor, HSCARG (NmrA (34-36)-like family domain containing protein 1), is shown to negatively regulate NF-kB function. 39, 40 Furthermore, the dual oxidase-derived oxidative burst is essential for extracellular matrix modification of sea urchin eggs during fertilization. [41] [42] [43] Still more, it has been reported that ROS can negatively regulate Ras/MAPK pathway. 44 In addition, p38 and ERK/MAPK have been shown to block bovine preimplantation embryogenesis. 45 In order to clarify the role of MAPK in G6PD knockdown-induced defective hatching, we proposed a mechanism (Figure 8b ) in which the depletion of G6PD-derived NADPH reduces the activity of the unknown NADPH sensor (for example, dual oxidase 46 ) in C. elegans. The decreased ROS signaling (represents as low oxidative stress, in contrast to high oxidative stress that causes defective egg production in G6PD deficiency) activates MAPK activity through negative regulation. In turn, the activated MAPK impairs the hatching possibly through multiple signal transduction pathways. Hence, the inactivation of mek-1 or sek-1 negates the deleterious effects on hatching caused by G6PD knockdown in C. elegans. Indeed, the role of MAPK signaling in antagonizing essential gene for embryogenesis has been documented. The loss-of-function of MAPK pathways, including lin-45 (RAF), mek-2 (MEK), and mpk-1 (ERK), differentially rescue embryonic lethality of par-1 (partitioning defective) mutant embryos. 47 However, how does the inactivation of sek-1 or mek-1 actually suppress the defective hatching induced by G6PD knockdown remains to be elucidated.