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Mechanisms involved in the control of body size are largely unknown. In the nematode C. elegans, several small body size mutants were isolated, and the responsible genes were reported to encode putative components of a TGFβ signalling pathway. Recently, mutants in the egl-4 gene encoding cGMP-dependent protein kinases were found to have a larger body size, and it was suggested that EGL-4 down-regulates the TGFβ/DBL-1 pathway. We show that a permeable cGMP analogue 8-Br-cGMP significantly reduces body size of the wild-type but not that of an egl-4 mutant, indicating that cGMP controls body size through EGL-4. Laser ablation of germ-line cells revealed that a germ-line signal and EGL-4 function in the same pathway. Targeted expression of EGL-4 indicates that EGL-4 can function in hypodermis, neurones and intestine both cell-autonomously and cell-nonautonomously to control organ and body size. We propose a signal cascade for the control of body size that involves a germ-line signal, cGMP, G-kinase EGL-4 and DBL-1/TGFβ pathway. It is interesting that two important pathways involving cGMP and TGFβ, respectively, are related. Also, the results suggest a novel mechanism for the control of organ and body size in which hypodermis plays a key role [ABSTRACT FROM AUTHOR]

We recently showed that egl-4 mutants in Caenorhabditis elegans have a much larger body size and that the egl-4 gene encodes cyclic GMP-dependent protein kinases (G-kinases). Cell sizes, but not cell numbers, in the major organs are increased in the mutants. Genetic interaction studies suggest that EGL-4 represses the DBL-1/TGFβ pathway that is known to control body size. To understand the mechanisms of body size control in C. elegans, we analysed sma-2, sma-4 and sma-6 small mutants in the DBL-1 pathway. The volumes of major organs were precisely determined with the method developed by us. They are significantly decreased as compared to those of the wild-type while cell numbers are not, indicating that cell size is decreased. DNA contents in the nuclei of major organs are not significantly changed in the small mutants and in an egl-4 large mutant. Total protein contents are much decreased in the small mutants and slightly increased in the egl-4 mutant. Based on these results, we propose that decreased cell and body size of the small mutants in the DBL-1/TGFβ pathway is mainly due to decreased levels of protein expression, and that increase in fluid content is a major reason for the increase in cell and body size in egl-4 mutants. [ABSTRACT FROM AUTHOR]