Myotubularins (MTMs) constitute a large family of lipid phosphatases that 
specifically dephosphorylate phosphatidylinositol (3)P. MTM1 and MTM2 are 
mutated in X-linked myotubular myopathy and Charcot-Marie-Tooth disease (type 
4B), respectively, although the mechanisms whereby MTM dysfunction leads to 
these diseases is unknown. To gain insight into MTM function, we undertook the 
study of MTMs in the nematode Caenorhabditis elegans, which possesses 
representative homologues of the four major subgroups of MTMs identified in 
mammals. As in mammals, we found that C. elegans MTMs mediate distinct 
functions. let-512 (vps34) encodes the C. elegans homologue of the yeast and 
mammalian homologue of the phosphatidylinositol 3-kinase Vps34. We found that 
reduction of mtm-6 (F53A2.8) function by RNA inhibition rescued the larval 
lethality of let-512 (vps34) mutants and that the reduction of mtm-1 (Y110A7A.5) 
activity by RNA inhibition rescued the endocytosis defect of let-512 animals. 
Together, these observations provide genetic evidence that MTMs negatively 
regulate phosphatidylinositol (3)P levels. Analysis of MTM expression patterns 
using transcriptional green fluorescence protein reporters demonstrated that 
these two MTMs exhibit mostly non-overlapping expression patterns and that 
MTM-green fluorescence protein fusion proteins are localized to different 
subcellular locations. These observations suggest that some of the different 
functions of MTMs might, in part, be a consequence of unique expression and 
localization patterns. However, our finding that at least three C. elegans MTMs 
play essential roles in coelomocyte endocytosis, a process that also requires 
VPS34, indicates that MTMs do not simply turn off VPS34 but unexpectedly also 
function as positive regulators of biological processes.