Sensory and metabolic regulation of stem cell niche function

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The mechanisms by which food abundance modifies development and reproduction are not well understood. We identified a “neuron-to-niche” (TGFß-to-Notch) signaling mechanism in C. elegans that provides an unprecedented opportunity to determine how the food environment promotes the expansion of a stem cell pool during development. Specifically, we found that DAF-7/TGFß signaling from ASI neurons promotes the accumulation of germline stem cells during the period of development just prior to reproductive maturity. This regulation differs in fundamental ways from previously described roles for DAF-7/TGFß, including tissue- requirement for the TGFß receptor and downstream genetic dependencies. In the neuron-to- niche system, the TGFß receptor is required in the stem cell niche for the response to abundant food. There, the TGFß receptor pathway regulates the transcription of lag-2, a gene that encodes a ligand for the Notch receptor that is expressed in nearby germline stem cells. Notch activity in the germline stem cells prevents their differentiation and thereby facilitates their accumulation during development. Therefore, food – via neuronal TGFß – regulates the expression of a critical factor in the stem cell niche such that abundant food expands the germline stem cell pool. We will take advantage of the tools and features of C. elegans (including defined anatomy, sophisticated genetics, single-cell resolution, facile dietary manipulation, and live imaging), and the quantitative readout of lag-2 expression in the niche, to further elucidate the mechanistic underpinnings of this neuron-to-niche system. We will determine (i) the molecular mechanisms of TGFß signaling from the neurons that convey differences in food quantity, (ii) the quantitative relationship between neuronal TGFß and the niche lag-2 response, (iii) the role of sensory activity of the neuron (versus other neuromodulatory or metabolic inputs) (iv) the sensitivity and dynamics of the niche response to altered food abundance, and (v) the components of the microbial environment (sensory and/or nutritive) that regulate TGFß signaling-dependent lag-2 expression. The molecular pathways that work in this system are highly conserved and are implicated in stem cell biology and human disease states, especially cancer. Therefore, the project will advance basic scientific knowledge, with implications for many general medical areas, including fertility, cancer, and regenerative medicine.