The long-term objective of my laboratory is a detailed molecular understanding of how cell fates are regulated by division sequence and cell signaling in animal development. During C. elegans embryogenesis, Wnt and MAP kinase signaling pathways specify the endoderm precursor E. We showed that Wnt increases the level of 2-catenin/SYS and MAP kinase reduces the level of TCF/POP-1, together robustly increasing the SYS-1-to-POP ratio and transcriptional activation of endoderm genes in E. In the anterior sister of E, MS, the SYS-1-to-POP-1 ratio is low and endoderm genes are repressed. We observed the asymmetric SYS-1-to-POP-1 ratio in all A-P divisions examined and showed that it is required for all A-P fate differences examined. Studies from us and others have suggested that the MAP kinase pathway also regulates POP-1 activity, in addition to its nuclear levels. The overall objective of this proposal is to understand how phosphorylation by the MAP kinase complex, LIT-1/WRM-1, affects POP-1 activity, how POP-1 sequence itself influence its phosphorylation by LIT-1/WRM-1, and how the information in division sequence is mechanistically linked to the activation of the MAP kinase pathway. The hypotheses to be tested are: (1) LIT-1/WRM-1 regulates POP-1 activity by increasing its binding to SYS-1, in addition to reducing its nuclear levels. (2) LIT-1/WRM-1 regulates POP-1 nuclear levels and transcription activity by phosphorylating two distinct sets of sites whose phosphorylation are mutually exclusive and inhibited by each other. (3) The C-terminal domain of POP-1 promotes LIT-1/WRM-1 phosphorylation by bringing POP-1 to the kinase complex and/or presenting the phosphorylation sites. (4) The upstream regulators for the MAPK pathway also regulate spindle rotation and division axes.
The specific aims are: (1) To investigate the mechanism by which LIT-1/WRM-1 coordinately regulate POP-1 nuclear level and activity. We will identify sites whose phosphorylation enhances POP-1 transcription activity. We will investigate the interactive regulation between phosphorylation sites that lower nuclear levels or increase transcriptional activation. (2) To investigate the mechanism by which the C-terminal 39 amino acids of POP-1 regulate phosphorylation by LIT-1. We will perform biochemical analyses to test models for how the POP-1 C-terminal 39 amino acids might regulate POP- 1 phosphorylation by LIT-1/WRM-1. (3) To identify additional genes in the MOM-4/LIT-1/WRM-1 MAPK pathway. RNAi screens will be performed in a background highly sensitized for defects in this pathway. We will also specifically investigate genes known to regulate cell division axes for their possible role(s) in activating this pathway. Misregulation of division axes or signaling pathways can lead to developmental defects or cancer. These experiments will aid our understanding of these processes.

Public Health Relevance

Colorectal cancer causes more than 50,000 deaths annually in the US, and greater than 90% of these cancers are caused by activating mutations in the Wnt signaling pathway. Our ability to detect, diagnose and treat these cancers (as well as other cancer types and embryological defects caused by deregulated Wnt signaling) will rely heavily upon our understanding of this pathway, its components and their normal regulation. This proposal aims to significantly broaden our understanding of the Wnt signaling pathway, and how it intersects with other signaling pathways during development.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Development - 2 Study Section (DEV2)
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Mukhopadhyay, Mahua
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University of Texas Sw Medical Center Dallas
Schools of Medicine
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Robertson, Scott M; Medina, Jessica; Oldenbroek, Marieke et al. (2017) Reciprocal signaling by Wnt and Notch specifies a muscle precursor in the C. elegans embryo. Development 144:419-429
Yang, Xiao-Dong; Karhadkar, Tejas R; Medina, Jessica et al. (2015) ?-Catenin-related protein WRM-1 is a multifunctional regulatory subunit of the LIT-1 MAPK complex. Proc Natl Acad Sci U S A 112:E137-46
Robertson, Scott; Lin, Rueyling (2015) The Maternal-to-Zygotic Transition in C. elegans. Curr Top Dev Biol 113:1-42
Robertson, Scott M; Medina, Jessica; Lin, Rueyling (2014) Uncoupling different characteristics of the C. elegans E lineage from differentiation of intestinal markers. PLoS One 9:e106309
Spike, Caroline A; Coetzee, Donna; Nishi, Yuichi et al. (2014) Translational control of the oogenic program by components of OMA ribonucleoprotein particles in Caenorhabditis elegans. Genetics 198:1513-33
Robertson, Scott; Lin, Rueyling (2013) The oocyte-to-embryo transition. Adv Exp Med Biol 757:351-72
Oldenbroek, Marieke; Robertson, Scott M; Guven-Ozkan, Tugba et al. (2013) Regulation of maternal Wnt mRNA translation in C. elegans embryos. Development 140:4614-23
Oldenbroek, Marieke; Robertson, Scott M; Guven-Ozkan, Tugba et al. (2012) Multiple RNA-binding proteins function combinatorially to control the soma-restricted expression pattern of the E3 ligase subunit ZIF-1. Dev Biol 363:388-98
Yang, Xiao-Dong; Huang, Shuyi; Lo, Miao-Chia et al. (2011) Distinct and mutually inhibitory binding by two divergent ?-catenins coordinates TCF levels and activity in C. elegans. Development 138:4255-65
Robertson, Scott M; Lo, Miao-Chia; Odom, Ranaan et al. (2011) Functional analyses of vertebrate TCF proteins in C. elegans embryos. Dev Biol 355:115-23

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