How animals regulate growth, development and behaviors in response to changes in nutrient availability and metabolic status is a fundamental biological problem that is closely related to human diseases and health. While major advances have been made over the last decade in understanding TOR, insulin receptor and other signaling systems that sense the levels of sugar and amino acids to control various cellular and physiological functions, the study of the mechanisms by which cells and animals respond to changes in nucleotide levels to regulate development and other physiological functions is lacking, even though nucleotide levels have been shown to impact several cellular processes including cancer progression and certain human disorders. The goal of this proposal is to discover and analyze the mechanism of such a nucleotide-responsive regulatory system. By using genes involved in nucleotide metabolism in both sthe worm and its food source E. coli, we have established a unique model system where we observe a profound impact of uridine and thymidine (referred to as U/T) on germline development. Results from our preliminary study, including a suppressor screen, have indicated two key factors in the U/T sensing system leading to the hypothesis that an unknown system involving a ribonuclease acts upstream of a Notch signaling pathway to regulate germline proliferation and pyrimidine metabolic pathways. We will test this hypothesis by studies under three specific aims: (1) determine how Notch receptor (glp-1) expression is regulated by U/T levels, including the identification of the U/T-responsive element and potential upstream regulator; (2) determine if a novel ribonuclease (scdd-1), identified from our genetic screen, mediates the impact of U/T level on glp-1 expression; (3) investigate the potential regulation of pyrimidine metabolic pathways by U/T levels scdd-1; and (4) investigate the mechanism of scdd-1 function. By connecting nucleotide availability to developmental programs and metabolism, the results from these studies will likely present an important conceptual advance in the fields of nucleotide metabolism, development and nutritional science. Such findings may also provoke others to evaluate the impact of nucleotide quality in food or nutritional supplements on human health, especially for those with genetic risks for certain metabolic diseases.
How animals regulate growth and development in response to changes in nucleotide levels is an important but grossly under-explored biological problem related to human health problems, including cancers. Research under this proposal is expected to reveal a cellular signaling system that regulates germ cell development in response to changes in the uridine/thymidine cellular pool that reflects the quality of food and endogenous metabolic status. !
|Weaver, Benjamin P; Han, Min (2018) Tag team: Roles of miRNAs and Proteolytic Regulators in Ensuring Robust Gene Expression Dynamics. Trends Genet 34:21-29|
|Cui, Mingxue; Wang, Yi; Cavaleri, Jonathon et al. (2017) Starvation-Induced Stress Response Is Critically Impacted by Ceramide Levels in Caenorhabditis elegans. Genetics 205:775-785|
|Zabinsky, Rebecca A; Weum, Brett M; Cui, Mingxue et al. (2017) RNA Binding Protein Vigilin Collaborates with miRNAs To Regulate Gene Expression for Caenorhabditis elegans Larval Development. G3 (Bethesda) 7:2511-2518|
|Weaver, Benjamin P; Weaver, Yi M; Mitani, Shohei et al. (2017) Coupled Caspase and N-End Rule Ligase Activities Allow Recognition and Degradation of Pluripotency Factor LIN-28 during Non-Apoptotic Development. Dev Cell 41:665-673.e6|
|Chi, Congwu; Ronai, Diana; Than, Minh T et al. (2016) Nucleotide levels regulate germline proliferation through modulating GLP-1/Notch signaling in C. elegans. Genes Dev 30:307-20|
|Cohen, Max L; Kim, Sunhong; Morita, Kiyokazu et al. (2015) The GATA factor elt-1 regulates C. elegans developmental timing by promoting expression of the let-7 family microRNAs. PLoS Genet 11:e1005099|
|Weaver, Benjamin P; Zabinsky, Rebecca; Weaver, Yi M et al. (2014) CED-3 caspase acts with miRNAs to regulate non-apoptotic gene expression dynamics for robust development in C. elegans. Elife 3:e04265|
|Than, Minh T; Kudlow, Brian A; Han, Min (2013) Functional analysis of neuronal microRNAs in Caenorhabditis elegans dauer formation by combinational genetics and Neuronal miRISC immunoprecipitation. PLoS Genet 9:e1003592|
|Than, Minh; Han, Min (2013) Functional analysis of the miRNA-mRNA interaction network in C. elegans. Worm 2:e26894|
|Cui, Mingxue; Cohen, Max L; Teng, Cindy et al. (2013) The tumor suppressor Rb critically regulates starvation-induced stress response in C. elegans. Curr Biol 23:975-80|
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