Growth in C. elegans is regulated by a group of eight chemosensory neurons that have endings that are directly exposed to the external environment. When nutrients are abundant, these neurons secrete into the body fluid insulin-like growth factors, including DAF-28 and INS-4, and a ligand in the TGFb superfamily, DAF-7.
In target cells throughout the organism, DAF-28, INS-4 and DAF-7 promote growth leading to the normal (reproductive) life cycle. Mutants lacking activity of the insulin-like signaling pathway (or DAF-7) enter a long-lived, alternative developmental stage termed dauer in which they do not reproduce. Mutations affecting the synthesis or secretion of DAF-28, INS-4 or DAF-7 also cause inappropriate entry into dauer. Work in a number of labs has shown that secretion of insulin-like proteins in C. elegans requires proteins that regulate the secretion of insulin from b-cells in vertebrates. The ability to perform large-scale genetic screens for mutations affecting entry into dauer thus provides a powerful tool with which to investigate how the synthesis and secretion of TGFb and insulin-like growth factors are regulated in metazoans. Work in our lab has shown that ASNA-1, a conserved ATPase, acts in chemosensory neurons to promote the secretion of DAF-28. We are presently investigating other molecules that promote growth in C. elegans by stimulating the production of DAF-7, DAF-28 or INS-4.
A fundamental question in Biology is how organisms regulate their size in response to changing nutrient availability. A second TGFb-family ligand in C. elegans, DBL-1, does not control entry into dauer but instead regulates body size. Unlike that of DAF-7, the expression of DBL-1 is not restricted to chemosensory neurons but is more widely expressed within the nervous system. Loss of DBL-1 activity causes a dramatic reduction in body size whereas elevated levels of DBL-1 cause a two-fold increase in body length. In order to investigate how the synthesis and secretion of DBL-1 are controlled (and how the TGFb signaling pathway it activates functions) we have performed genetic screens for mutants with altered body size. We have shown that one protein important for correct body size is LON-3. We are presently working to characterize other genes identified in our screen.
Besides controlling entry into dauer, the pathways activated by DAF-28, DAF-7 and INS-4 also control fat metabolism. Worms with reduced DAF-7 activity (or reduced insulin signaling activity) accumulate triglycerides in adipose tissue. We have identified a number of mutants with altered fat metabolism that function either downstream of or in parallel to the TGFb and insulin-like signaling pathways. We believe that the characterization of these mutants will help in the understanding of how fat metabolism is regulated in metazoans. We have recently shown that C. elegans worms lacking TAT-1, a putative phospholipids translocase, have much reduced fat accumulation and that this defect is associated with defects in lysosomal biogenesis.