Non-autonomous regulation of germline stem cell proliferation by somatic MPK-1/MAPK activity in C. elegans.

Extracellular-signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) is a major positive regulator of cell proliferation, which is often upregulated in cancer. However, few studies have addressed ERK/MAPK regulation of proliferation within a complete organism. The Caenorhabditis elegans ERK/MAPK ortholog MPK-1 is best known for its control of somatic organogenesis and germline differentiation, but it also stimulates germline stem cell proliferation. Here, we show that the germline-specific MPK-1B isoform promotes germline differentiation but has no apparent role in germline stem cell proliferation. By contrast, the soma-specific MPK-1A isoform promotes germline stem cell proliferation non-autonomously. Indeed, MPK-1A functions in the intestine or somatic gonad to promote germline proliferation independent of its other known roles. We propose that a non-autonomous role of ERK/MAPK in stem cell proliferation may be conserved across species and various tissue types, with major clinical implications for cancer and other diseases.