Identification and characterization of new factors involved in feedback regulation of stem cell proliferation

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Stem cells are amongst the most important cells in the human body. They are relatively undifferentiated cells that have the capacity to proliferate and expand in numbers, while they can also differentiate into more specialized cell types. From the embryonic stem cells to the plethora of adult (tissue-specific) stem cells, they are essential to the generation and regeneration of our tissues and organs.***How these critical cells function and how they are regulated has therefore been the focus of intensive investigation. Particularly key was the discovery of the stem cell niche, which provides a spatially restricted environment in which stem cells are maintained in their proliferative, undifferentiated state. Niche-resident stem cells thus uniquely have the capacity to proliferate and expand in numbers, although they can also exist there in an inactive or quiescent state. Whether stem cells remain quiescent or proliferate is the result of the integration of the growth factors that they receive from various sources.***One important such growth factor is an insulin/IGF-1 signal that is systemically distributed to stimulate the proliferation of most (if not all) stem cells following nutrient uptake. Yet, not all stem cell populations across and within an animal's tissues equally respond to this signal, such that at any one time: some stem cell populations may proliferate, but others may not. We, and others, found evidence that stem cell proliferation is adjusted locally by homeostatic signals originating from the stem cells' differentiated progeny. This feedback signal is generated by the need for newly differentiated cells in a tissue, to replace old or damaged cells. As such, when no new differentiated cells are needed in a given tissue, such feedback signals locally antagonize insulin/IGF-1 and block proliferation of the parental stem cell population. How a tissue's needs for new differentiated cells overrides the systemic insulin/IGF-1 signal to locally adjust adult SC proliferation rates is a major unsolved problem in biology.***Through a new screening method that we have developed in a convenient, well-characterized invertebrate model (C. elegans), we have isolated 5 new alleles that specifically prevent homeostatic regulation of germline stem cell proliferation. We found that one of these mutations affects an extracellular matrix protein called Papilin. We aim to resolve how Papilin, the extracellular matrix and four new factors participate in feedback stem cell regulation through the following three specific objectives:***1) Establish the role of Papilin in homeostatic regulation of GSC proliferation.***2) Define Papilin's PLAC domain-mediated interaction network in homeostatic GSC regulation.***3) Clone and characterize four new mutations implicated in homeostatic GSC regulation.***In line with NSERC's mandate, the broad goal of the proposed research is thus to expand our fundamental knowledge about the in vivo mechanisms that regulate stem cell activity.