Basal cytoplasmic calcium levels regulate C. elegans germ stem cell proliferation

The C. elegans germline is one of the foremost model systems for the study of germ cell biology. We have created an integrated ratiometric calcium reporter that allows comparative analysis of calcium levels in germ cells. We observe a positive correlation between the rate of cell proliferation and calcium levels. Conditions that decrease proliferation decrease basal cytoplasmic calcium levels, these include starvation and loss of insulin, TGF-β, and folate signaling. Conversely, overproliferating germline tumor cells have increased basal cytoplasmic calcium levels. To determine if basal calcium levels regulate the rate of proliferation, we decreased calcium levels by inactivating the TRPM7-related GON-2 calcium channel. A gon-2 null mutant has significantly decreased basal cytoplasmic calcium levels and germ cell proliferation. Partial reduction of GON-2 activity in a gon-2 mutant heterozygote also reduces calcium levels and proliferation, but to a lower extent. This identifies GON-2 as a calcium channel that is required to maintain basal cytoplasmic calcium levels in germ cells. Conversely, increasing basal cytoplasmic calcium levels in germ cells either by inhibiting the plasma membrane calcium ATPase (which transports cytoplasmic calcium out of cells) or by inhibiting the SERCA channel (which transports cytoplasmic calcium into the endoplasmic reticulum) increased basal calcium levels and germ cell proliferation. This study identifies the germ line as the first tissue in C. elegans whose rate of cell proliferation is regulated by calcium. While transient increases in calcium are associated with cell proliferation in many animal species, our study suggests that the basal level of cytoplasmic calcium acts as a rheostat to modulate the rate of C. elegans germ cell proliferation in response to physiological processes and signals.