Developmental decisions are controlled by the combined action of multiple regulatory pathways. One critical aspect of regulation is the controlled timing of the onset of specific developmental programs that render cells competent for responding to other signals. Our goal is to understand the genetic and biochemical mechanisms by which several genes regulate developmental timing and to understand the link between the regulatory pathway and specific cellular events such as cell divisions and differentiations. Research under this grant has used C. elegans vulval induction as a model system to investigate the functions and interactions of multiple pathways, including the Ras-MAP kinase pathway. Recently, by searching for genes acting downstream of Ras signaling, we have identified four genes that are involved in regulating the timing of vulval cell divisions. Among them, LIN-66 represses the expression of a key timing regulator LIN-28, and AIN-1 binds to ALG-1, Dicer and microRNA of the microRNA induced complexes (miRICS) and targets ALG-1 to specific cytoplasmic foci. A transcription factor LIN-31 that acts downstream of Ras-MAPkinase is also involved in timing regulation. We will carry out a series molecular and genetic experiments to understand how LIN-66 regulates lin-28 expression and what biochemical properties AIN-1 provides to miRISCs. Through identifying the miRNAs and their targets associated with AIN-1, we will determine if AIN-1 is associated with only a subset of miRNAs for their functions, as well as learning about these specific functions carried by these targets. We also plan to study the functions of AIN-2, which has structural and functional similarities to AIN-1, as well as two other genes. Finally, we will search for targets of LIN-31 to learn about what factors execute the regulatory role of LIN-31 in timing regulatory and in mediated Ras signaling. microRNA functions and Ras signaling are conserved between worms and human, and are involved in many human developmental processes and diseases, such as cancers. Studies in C. elegans have made a huge impact on the research in related fields. The proposed research intends to provide new insights into cellular processes involved in these newly identified genes. ? ? ?

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Development - 1 Study Section (DEV1)
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Haynes, Susan R
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University of Colorado at Boulder
Schools of Arts and Sciences
United States
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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
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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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