Mutations in
clk-1 cause an average slowing down of development, rhythmic behaviors and aging (1, 2). Here, we show that
clk-1 is also required for the coordinated development of the somatic tissue and the germline. Mutations in
clk-1 result in the retarded development of the germline relative to that of soma.
dsc-4, originally isolated as a suppressor of the defecation phenotypes of
clk-1 (3) also suppresses the germline phenotypes of
clk-1 mutants.
dsc-4, which is expressed in the gut, encodes the large subunit of the C.elegans microsomal triglyceride transfer protein (MTP). In vertebrates, MTP is required for the assembly and secretion of apoB-containing lipoprotein. We have found that, like mutations in
dsc-4, RNA interference (RNAi) against
vit-3, -4 and -5, which encode the worm homologues of vertebrate apoB, can also suppress the slow germline development. Together, these results suggest that lipoprotein secretion from the gut is involved in regulating the rate of germline development. CLK-1 is necesary for ubiquinone (UQ) biosynthesis. In
clk-1 mutants, UQ is replaced by the biosynthetic intermediate, demethoxyubiquinone (DMQ) (4). The redox properties of DMQ are quantitatively different from those of UQ, in particular, DMQ might be less prone to ROS production than UQ (5). If the developmental timing of the germline is redox-regulated and the redox properties of DMQ result in less oxidative stress than UQ, reducing the function of antioxidant enzymes such as the superoxide dismutases (SOD) could suppress the abnormal timing of germline development by increasing the amount of ROS. Indeed, we find that RNAi against the cytoplasmic Cu/Zn sod,
sod-1 can suppress the slow germline development of
clk-1 mutants. As the slow development of the germline can be relieved by increasing the amount of superoxide generated in the cytoplasm, these results suggest that slow germline development of
clk-1 mutants is due to low levels of ROS. We also used the
sid-1 mutant, in which RNA interference does not spread from tissue to tissue, to show that
sod-1(RNAi) acts in the gut in suppressing slow germline development. Together with the findings that the cytoplasmic Cu/Zn-SOD regulates the level of LDL oxidation in other systems, this observation suggests that the oxidation of lipoproteins is an important factor in controlling the development of the germline. We propose that native lipoproteins inhibit, while oxidized lipoproteins stimulate germline development in C.elegans. (1) Wong et al, Genetics. 1995 139:1247-59. (2) Lakowski et al, Science. 1996 272:1010-3 (3) Branicky et al., Genetics. 2001 159:1006 (4) Miyadera et al, J Biol Chem. 2001 276:7713-6 (5) Miyadera et al., FEBS Lett. 2002 512:33-7.