Gene Symbol: pha-4
Description: Defective pharyngeal development protein 4
Alias: Defective pharyngeal development protein 4
Species: Caenorhabditis elegans

Top Publications

  1. Greer E, Brunet A. Different dietary restriction regimens extend lifespan by both independent and overlapping genetic pathways in C. elegans. Aging Cell. 2009;8:113-27 pubmed publisher
    ..Understanding the genetic network by which different DR regimens extend lifespan has important implications for harnessing the full benefits of DR on lifespan and healthspan. ..
  2. Lapierre L, Gelino S, Melendez A, Hansen M. Autophagy and lipid metabolism coordinately modulate life span in germline-less C. elegans. Curr Biol. 2011;21:1507-14 pubmed publisher
    ..Collectively, our data offer a novel mechanism by which autophagy and the lipase LIPL-4 interdependently modulate aging in germline-deficient C. elegans by maintaining lipid homeostasis to prolong life span. ..
  3. Zhong M, Niu W, Lu Z, Sarov M, Murray J, Janette J, et al. Genome-wide identification of binding sites defines distinct functions for Caenorhabditis elegans PHA-4/FOXA in development and environmental response. PLoS Genet. 2010;6:e1000848 pubmed publisher
    ..These results indicate distinct roles for this regulator in two different biological processes and demonstrate the versatility of transcription factors in mediating diverse biological roles. ..
  4. Sheaffer K, Updike D, Mango S. The Target of Rapamycin pathway antagonizes pha-4/FoxA to control development and aging. Curr Biol. 2008;18:1355-64 pubmed publisher
    ..A similar regulatory hierarchy may function in other animals to modulate metabolism, longevity, or disease. ..
  5. Mango S, Lambie E, Kimble J. The pha-4 gene is required to generate the pharyngeal primordium of Caenorhabditis elegans. Development. 1994;120:3019-31 pubmed
    ..We propose that pha-4 marks a convergence of the inductive and autonomous pathways of pharyngeal development and suggest that establishment of pharyngeal organ identity is a crucial step for pharyngeal organogenesis. ..
  6. Vilimas T, Abraham A, Okkema P. An early pharyngeal muscle enhancer from the Caenorhabditis elegans ceh-22 gene is targeted by the Forkhead factor PHA-4. Dev Biol. 2004;266:388-98 pubmed
    ..Because de209 enhancer activity is primarily limited to the pharyngeal muscles, we hypothesize that de209 also binds factors functioning with PHA-4 to specifically activate ceh-22 expression in pharyngeal muscle. ..
  7. Kiefer J, Smith P, Mango S. PHA-4/FoxA cooperates with TAM-1/TRIM to regulate cell fate restriction in the C. elegans foregut. Dev Biol. 2007;303:611-24 pubmed
    ..We propose that restriction of early blastomeres to the pharyngeal fate depends on both repression of ectodermal genes and activation of pharyngeal genes by PHA-4. ..
  8. Panowski S, Wolff S, Aguilaniu H, Durieux J, Dillin A. PHA-4/Foxa mediates diet-restriction-induced longevity of C. elegans. Nature. 2007;447:550-5 pubmed
    ..elegans. The role of PHA-4 in lifespan determination is specific for dietary restriction, because it is not required for the increased longevity caused by other genetic pathways that regulate ageing. ..
  9. Smith Vikos T, de Lencastre A, Inukai S, Shlomchik M, Holtrup B, Slack F. MicroRNAs mediate dietary-restriction-induced longevity through PHA-4/FOXA and SKN-1/Nrf transcription factors. Curr Biol. 2014;24:2238-46 pubmed publisher
    ..elegans. Given the conservation of miRNAs, PHA-4, and SKN-1 across phylogeny, these interactions are likely to be conserved in more-complex species. ..

More Information


  1. Kaltenbach L, Updike D, Mango S. Contribution of the amino and carboxyl termini for PHA-4/FoxA function in Caenorhabditis elegans. Dev Dyn. 2005;234:346-54 pubmed
    ..We suggest that the PHA-4 amino terminus is essential for PHA-4 function in vivo, possibly as a transactivation domain, and can compensate for loss of the carboxyl terminus. We also provide evidence for autoregulation by PHA-4. ..
  2. Updike D, Mango S. Temporal regulation of foregut development by HTZ-1/H2A.Z and PHA-4/FoxA. PLoS Genet. 2006;2:e161 pubmed
    ..Thus, the effects of PHA-4 on temporal regulation can be explained in part by recruitment of HTZ-1 to target promoters. We suggest PHA-4 and HTZ-1 coordinate temporal gene expression by modulating the chromatin environment. ..
  3. Updike D, Mango S. Genetic suppressors of Caenorhabditis elegans pha-4/FoxA identify the predicted AAA helicase ruvb-1/RuvB. Genetics. 2007;177:819-33 pubmed
    ..A second suppressor defined a new locus, the predicted AAA+ helicase ruvb-1. These results indicate that our screen successfully found cis- or trans-acting regulators of pha-4. ..
  4. Kalb J, Lau K, Goszczynski B, Fukushige T, Moons D, Okkema P, et al. pha-4 is Ce-fkh-1, a fork head/HNF-3alpha,beta,gamma homolog that functions in organogenesis of the C. elegans pharynx. Development. 1998;125:2171-80 pubmed
    ..Overall, our results provide evidence for a highly conserved pathway regulating formation of the digestive tract in all (triploblastic) metazoa. ..
  5. Ao W, Gaudet J, Kent W, Muttumu S, Mango S. Environmentally induced foregut remodeling by PHA-4/FoxA and DAF-12/NHR. Science. 2004;305:1743-6 pubmed
    ..Our combination of bioinformatics and in vivo analysis has provided a powerful means for genome-wide investigation of transcriptional control. ..
  6. Fakhouri T, Stevenson J, Chisholm A, Mango S. Dynamic chromatin organization during foregut development mediated by the organ selector gene PHA-4/FoxA. PLoS Genet. 2010;6: pubmed publisher
    ..We speculate that global re-organization of chromatin architecture upon PHA-4 binding promotes competence of pharyngeal gene transcription and, by extension, foregut development. ..
  7. van Oosten Hawle P, Porter R, Morimoto R. Regulation of organismal proteostasis by transcellular chaperone signaling. Cell. 2013;153:1366-78 pubmed publisher
    ..This transcellular chaperone signaling response maintains organismal proteostasis when challenged by a local tissue imbalance in folding and provides the basis for organismal stress-sensing surveillance...
  8. Mosbech M, Kruse R, Harvald E, Olsen A, Gallego S, Hannibal Bach H, et al. Functional loss of two ceramide synthases elicits autophagy-dependent lifespan extension in C. elegans. PLoS ONE. 2013;8:e70087 pubmed publisher
    ..elegans lifespan. We propose that loss of HYL-1 and LAGR-1 result in dietary restriction-induced autophagy and consequently prolonged longevity. ..
  9. Ash P, Zhang Y, Roberts C, Saldi T, Hutter H, Buratti E, et al. Neurotoxic effects of TDP-43 overexpression in C. elegans. Hum Mol Genet. 2010;19:3206-18 pubmed publisher
    ..Our results demonstrate that in vivo TDP-43 neurotoxicity can result from nuclear activity of overexpressed full-length protein...
  10. Mouchiroud L, Molin L, Kasturi P, Triba M, Dumas M, Wilson M, et al. Pyruvate imbalance mediates metabolic reprogramming and mimics lifespan extension by dietary restriction in Caenorhabditis elegans. Aging Cell. 2011;10:39-54 pubmed publisher
    ..These findings suggest that inhibition of this transporter homolog in mammals might also promote a DR response. ..
  11. Rousakis A, Vlassis A, Vlanti A, Patera S, Thireos G, Syntichaki P. The general control nonderepressible-2 kinase mediates stress response and longevity induced by target of rapamycin inactivation in Caenorhabditis elegans. Aging Cell. 2013;12:742-51 pubmed publisher
    ..This is one step forward in the understanding of evolutionary conserved mechanisms that confer longevity and healthspan. ..
  12. O Rourke E, Kuballa P, Xavier R, Ruvkun G. ?-6 Polyunsaturated fatty acids extend life span through the activation of autophagy. Genes Dev. 2013;27:429-40 pubmed publisher
    ..We propose that the salubrious effects of dietary supplementation with ?-3/6 PUFAs (fish oils) that have emerged from epidemiological studies in humans may be due to a similar activation of autophagic programs. ..
  13. Nakamura S, Karalay Ã, Jäger P, Horikawa M, Klein C, Nakamura K, et al. Mondo complexes regulate TFEB via TOR inhibition to promote longevity in response to gonadal signals. Nat Commun. 2016;7:10944 pubmed publisher
    ..These studies reveal how an extensive interdependent HLH transcription factor network distributes responsibility and mutually enforces states geared towards reproduction or survival. ..
  14. Hsu H, Chen H, Yang Z, Wang J, Lee N, Burger A, et al. TRANSCRIPTION. Recruitment of RNA polymerase II by the pioneer transcription factor PHA-4. Science. 2015;348:1372-6 pubmed publisher
    ..Our results suggest that Pol II recruitment, in addition to chromatin opening, is an important feature of PHA-4 pioneer factor activity. ..
  15. Pandit A, Jain V, Kumar N, Mukhopadhyay A. PHA-4/FOXA-regulated microRNA feed forward loops during Caenorhabditis elegans dietary restriction. Aging (Albany NY). 2014;6:835-55 pubmed
  16. Cai L, Wang D, Fisher A, Wang Z. Identification of a genetic interaction between the tumor suppressor EAF2 and the retinoblastoma protein (Rb) signaling pathway in C. elegans and prostate cancer cells. Biochem Biophys Res Commun. 2014;447:292-8 pubmed publisher
    ..Together these findings identify a novel physical and functional interaction between EAF2 and the Rb pathway. ..
  17. Banerjee D, Slack F. Temporal and spatial patterning of an organ by a single transcription factor. Genome Biol. 2005;6:205 pubmed
    ..One such regulator, the nematode transcription factor PHA-4, functions together with various cis-regulatory elements in target genes to regulate spatial and temporal patterning during development of the pharynx. ..
  18. Raharjo W, Logan B, Wen S, Kalb J, Gaudet J. In vitro and in vivo characterization of Caenorhabditis elegans PHA-4/FoxA response elements. Dev Dyn. 2010;239:2219-32 pubmed publisher
    ..Third, in the context of some pharyngeal promoters, PHA-4 response elements are flanked by distinct cis-regulatory elements that modulate response to PHA-4, generating gene expression in specific pharyngeal cell types. ..
  19. Anokye Danso F, Anyanful A, Sakube Y, Kagawa H. Transcription factors GATA/ELT-2 and forkhead/HNF-3/PHA-4 regulate the tropomyosin gene expression in the pharynx and intestine of Caenorhabditis elegans. J Mol Biol. 2008;379:201-11 pubmed publisher
    ..Based on our data, PHA-4 and CdxA function as general transcription factors for pharyngeal and intestinal regulation of tmy-1. We present models by which ELT-2, PHA-4, and CdxA orchestrate expression from the internal promoter of tmy-1. ..
  20. Chen D, Thomas E, Kapahi P. HIF-1 modulates dietary restriction-mediated lifespan extension via IRE-1 in Caenorhabditis elegans. PLoS Genet. 2009;5:e1000486 pubmed publisher
    ..Therefore, our results demonstrate a tissue-specific role for HIF-1 in the lifespan extension by DR involving the IRE-1 ER stress pathway. ..
  21. Hibshman J, Hung A, Baugh L. Maternal Diet and Insulin-Like Signaling Control Intergenerational Plasticity of Progeny Size and Starvation Resistance. PLoS Genet. 2016;12:e1006396 pubmed publisher
    ..This work reveals maternal provisioning as an organismal response to DR, demonstrates potentially adaptive intergenerational phenotypic plasticity, and identifies conserved pathways mediating these effects. ..
  22. Park S, Link C, Johnson T. Life-span extension by dietary restriction is mediated by NLP-7 signaling and coelomocyte endocytosis in C. elegans. FASEB J. 2010;24:383-92 pubmed publisher
    ..We conclude that two novel pathways, NLP-7 signaling and endocytosis by coelomocytes, are required for life extension under dietary restriction in C. elegans. ..