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Gene Review

pha-4  -  Protein PHA-4

Caenorhabditis elegans

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High impact information on pha-4

  • Here we show that the pha-4 locus establishes organ identity for the Caenorhabditis elegans pharynx [1].
  • In pha-4 mutants, pharyngeal cells are transformed into ectoderm [1].
  • Conversely, ectopic pha-4 expression produces excess pharyngeal cells. pha-4 encodes an HNF-3 homolog selectively expressed in the nascent digestive tract, including all pharynx precursors at the time they are restricted to a pharyngeal fate [1].
  • We propose that it is the combination of pha-4 and regulatory molecules such as ceh-22 that produces the specific gene expression patterns during pharynx development [2].
  • Moreover, we show that pha-4 expression in the C. elegans gut is regulated by elt-2, a C. elegans gut-specific GATA-factor and possible homolog of the Drosophila gene serpent, which influences fork head expression in the fly gut [2].

Biological context of pha-4

  • pha-4 is Ce-fkh-1, a fork head/HNF-3alpha,beta,gamma homolog that functions in organogenesis of the C. elegans pharynx [2].
  • The C. elegans Ce-fkh-1 gene has been cloned on the basis of its sequence similarity to the winged-helix DNA binding domain of the Drosophila fork head and mammalian HNF-3alpha,beta,gamma genes, and mutations in the zygotically active pha-4 gene have been shown to block formation of the pharynx (and rectum) at an early stage in embryogenesis [2].
  • We describe the molecular characterization of five pha-4 mutations and characterize their associated phenotypes [3].
  • A missense mutation predicted to alter the PHA-4 amino terminus leads to a dramatic reduction in pha-4 activity even though the protein is expressed appropriately [3].
  • Most other tissues are generated normally in pha-4 mutants, including cells related to pharyngeal cells by cell lineage and position [4].

Anatomical context of pha-4

  • Multimerized de209 enhances transcription similarly to DE3 specifically in the pharyngeal muscles, suggesting it may be an essential site regulating ceh-22. de209 binds the pan-pharyngeal Forkhead factor PHA-4 in vitro and responds to ectopic pha-4 expression in vivo, suggesting that PHA-4 directly initiates ceh-22 expression through de209 [5].

Other interactions of pha-4

  • Our analysis suggests that a positive feedback loop between tbx-2 and pha-4 is required for ABa-derived precursors to commit to pharyngeal muscle fate [6].
  • We show that the nuclear hormone receptor daf-12 is a let-7 target in seam cells, while the forkhead transcription factor pha-4 is a target in the intestine [7].
  • Moreover, the pharynx/tail expression of the WGATAR-deleted ges-1 transgene is abolished by mutations in the zygotic gene pha-4 [8].
  • Inactivation of let-363/TOR or ruvb-1 suppresses the lethality associated with reduced pha-4 activity [9].


  1. pha-4, an HNF-3 homolog, specifies pharyngeal organ identity in Caenorhabditis elegans. Horner, M.A., Quintin, S., Domeier, M.E., Kimble, J., Labouesse, M., Mango, S.E. Genes Dev. (1998) [Pubmed]
  2. pha-4 is Ce-fkh-1, a fork head/HNF-3alpha,beta,gamma homolog that functions in organogenesis of the C. elegans pharynx. Kalb, J.M., Lau, K.K., Goszczynski, B., Fukushige, T., Moons, D., Okkema, P.G., McGhee, J.D. Development (1998) [Pubmed]
  3. Contribution of the amino and carboxyl termini for PHA-4/FoxA function in Caenorhabditis elegans. Kaltenbach, L.S., Updike, D.L., Mango, S.E. Dev. Dyn. (2005) [Pubmed]
  4. The pha-4 gene is required to generate the pharyngeal primordium of Caenorhabditis elegans. Mango, S.E., Lambie, E.J., Kimble, J. Development (1994) [Pubmed]
  5. An early pharyngeal muscle enhancer from the Caenorhabditis elegans ceh-22 gene is targeted by the Forkhead factor PHA-4. Vilimas, T., Abraham, A., Okkema, P.G. Dev. Biol. (2004) [Pubmed]
  6. Role of T-box gene tbx-2 for anterior foregut muscle development in C. elegans. Smith, P.A., Mango, S.E. Dev. Biol. (2007) [Pubmed]
  7. The temporal patterning microRNA let-7 regulates several transcription factors at the larval to adult transition in C. elegans. Grosshans, H., Johnson, T., Reinert, K.L., Gerstein, M., Slack, F.J. Dev. Cell (2005) [Pubmed]
  8. Modulation of gene expression in the embryonic digestive tract of C. elegans. Fukushige, T., Schroeder, D.F., Allen, F.L., Goszczynski, B., McGhee, J.D. Dev. Biol. (1996) [Pubmed]
  9. The Target of Rapamycin pathway antagonizes pha-4/FoxA to control development and aging. Sheaffer, K.L., Updike, D.L., Mango, S.E. Curr. Biol. (2008) [Pubmed]
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