My lab has had a long-standing interest in the molecular mechanisms that regulate organogenesis of the digestive tract. We have chosen a simple organ - the C. elegans pharynx (or foregut) - to identify the genes important for organ development and to understand how they function. Previously, we discovered the FoxA transcription factor homolog pha-4 as a critical regulator of pharyngeal development. However, PHA-4 alone cannot account for the diverse array of cell types within the pharynx. We hypothesize that regulators of organ identity act combinatorially with factors that control positional, blastomere, or cell type identity to establish patterns of gene expression within pharyngeal cells and thereby specify their fate. The goal of this study is to elucidate the regulatory network that generates different cell types within the C. elegans pharynx in combination with PHA-4.
Our Aims are i) to investigate the regulatory circuitry upstream of pha-4 by analyzing 14 genetic suppressors of partial loss of pha-4 function. We predict these mutants could fall into three classes and we have designed ways to distinguish between these classes. We will characterize the suppressors genetically and initiate a molecular analysis. ii) to determine the combinatorial code that .governs gene expression within the pharynx. We have identified 338 genes by microarray that are likely to be selectively expressed in the pharynx. We have grouped genes that are likely to be co-regulated within pharyngeal cells and are using computational approaches to identify cis-acting regulatory sites for these genes. Our goal is to determine the function of these sites in vivo and identify their trans-acting factors. We hypothesize that these elements will function combinatorially with PHA-4 binding sites to generate the diverse patterns of pharyngeal expression. iii) to extend the pathway for pharynx development using an RNA interference-based approach. We will survey the loss-of-function phenotypes associated with 295 candidate pharyngeal genes identified by microarray chip. Our goal is to discover genes that function downstream of PHA-4 to specify the fate of pharyngeal muscles. We will perform an in-depth analysis of those candidates that appear most promising.
|Hsu, H-T; Chen, H-M; Yang, Z et al. (2015) TRANSCRIPTION. Recruitment of RNA polymerase II by the pioneer transcription factor PHA-4. Science 348:1372-6|
|Von Stetina, Stephen E; Mango, Susan E (2015) PAR-6, but not E-cadherin and ?-integrin, is necessary for epithelial polarization in C. elegans. Dev Biol 403:5-14|
|Rosains, Jacqueline; Mango, Susan E (2012) Genetic characterization of smg-8 mutants reveals no role in C. elegans nonsense mediated decay. PLoS One 7:e49490|
|Meister, Peter; Mango, Susan E; Gasser, Susan M (2011) Locking the genome: nuclear organization and cell fate. Curr Opin Genet Dev 21:167-74|
|Zhong, Mei; Niu, Wei; Lu, Zhi John et al. (2010) Genome-wide identification of binding sites defines distinct functions for Caenorhabditis elegans PHA-4/FOXA in development and environmental response. PLoS Genet 6:e1000848|
|Fakhouri, Tala H I; Stevenson, Jeff; Chisholm, Andrew D et al. (2010) Dynamic chromatin organization during foregut development mediated by the organ selector gene PHA-4/FoxA. PLoS Genet 6:|
|Mango, Susan E (2009) The molecular basis of organ formation: insights from the C. elegans foregut. Annu Rev Cell Dev Biol 25:597-628|
|Yuzyuk, T; Fakhouri, T H I; Kiefer, J et al. (2009) The polycomb complex protein mes-2/E(z) promotes the transition from developmental plasticity to differentiation in C. elegans embryos. Dev Cell 16:699-710|
|Sheaffer, Karyn L; Updike, Dustin L; Mango, Susan E (2008) The Target of Rapamycin pathway antagonizes pha-4/FoxA to control development and aging. Curr Biol 18:1355-64|
|Von Stetina, Stephen E; Mango, Susan E (2008) Wormnet: a crystal ball for Caenorhabditis elegans. Genome Biol 9:226|
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