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Gene Review

bcd  -  bicoid

Drosophila melanogaster

Synonyms: BCD, BG:DS00276.7, Bcd, CG1034, Dmel\CG1034, ...
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Disease relevance of bcd

  • The posterior and anterior localization of Wolbachia resembles that of oskar and bicoid mRNAs, respectively, which define the anterior-posterior axis in the Drosophila oocyte [1].
  • These are used by the bicoid mRNA to form dimers, a property that appears to be important for mRNA localization in drosophila embryo, and by bacteriophage phi29 pRNA which forms hexamers that participate in the translocation of the DNA genome through the portal vertex of the capsid [2].
  • Other potentially useful RNA molecules that form multimers include HIV RNA that contain kissing loop to form dimers, tecto-RNA that forms a "jigsaw puzzle," and the Drosophila bicoid mRNA that forms multimers via "hand-by-arm" interactions [3].
  • Minimal inhibitory concentration values against mainly Gram-negative bacteria ranged from 3.1 to 100 mum [4].

High impact information on bcd

  • Translational inhibition depends on the Bcd binding region (BBR) present in the cad 3' untranslated region [5].
  • Drosophila bicoid mRNA is synthesized in the nurse cells and transported to the oocyte where microtubules and Exuperantia protein mediate localization to the anterior pole [6].
  • Furthermore, par-1 mutants show a novel polarity phenotype in which bicoid mRNA accumulates normally at the anterior, but oskar mRNA is redirected to the center of the oocyte, resulting in embryonic patterning defects [7].
  • Here we show that staufen protein colocalizes with bcd mRNA at the anterior, and that this localization depends upon its association with the mRNA [8].
  • Removal of both maternal and zygotic hb produces embryos with disrupted polarity that fail to express all known bcd target genes correctly [9].

Biological context of bcd

  • Implications for bcd mRNA localization from spatial distribution of exu protein in Drosophila oogenesis [10].
  • The localization of bicoid (bcd) messenger RNA to the anterior pole of the developing Drosophila oocyte gives rise in embryogenesis to a steep concentration gradient of the bcd protein, a transcription factor that activates expression of zygotic genes needed for anterior development [10].
  • In vitro manipulation of specific bcd protein binding sites has shown that the gradient of bcd protein can in principle define more than one discrete domain of spatially restricted gene activation in the head of the embryo, depending on the affinity of the available binding sites for the bcd protein [11].
  • Activation appears to depend on cooperative interactions among bcd and hb proteins, since disrupting single binding sites cause catastrophic reductions in expression. gt is directly involved in the formation of the anterior border, although additional repressors may participate in this process [12].
  • Quantitative analysis of gene expression in vivo indicated that bcd cooperativity mutants were unable to accurately direct the extent to which hb is expressed along the anterior-posterior axis and displayed a reduced ability to generate sharp on/off transitions for hb gene expression [13].

Anatomical context of bcd

  • We propose that the particles are ribonucleoprotein complexes or vesicles which transport bcd mRNA along microtubules and target it to the anterior oocyte cortex [10].
  • In mutant ovaries with duplicated polarity of microtubules, Swa and bcd RNA are ectopically localized at the posterior pole, as well as being present at the anterior pole [14].
  • We found that bicoid mutants specifically defective in cooperative DNA binding fail to direct proper development of the head and thorax, leading to embryonic lethality [13].
  • Anterior terminal development is controlled by several zygotic genes that are positively regulated at the anterior pole of Drosophila blastoderm embryos by the anterior (bicoid) and the terminal (torso) maternal determinants [15].
  • Using hb-promoter/lacZ fusion gene constructs in combination with germ line transformation, we have delimited a regulatory region for the 2.9-kb transcript to approximately 300 bp upstream of the site of transcription initiation and show that this region is sufficient to confer the full regulation by bcd [16].

Associations of bcd with chemical compounds

  • However, the bicoid mRNA in cortex embryos contains a shorter than normal polyadenosine (poly(A)) tail [17].
  • Bicoid is the founding member of the K50 class of homeodomain proteins, containing a lysine residue at the critical 50th position (K50) of the homeodomain sequence, a residue required for DNA and RNA recognition; Bcd also has an arginine residue at the 54th position (R54), which is essential for RNA recognition [18].
  • Exposure to cycloheximide or puromycin for 14 hr results in a 30 fold increase in the number of small circles per cell, but reduces the mean length of the circular DNA to 0.3 mum [19].
  • In particular, the guanine of X1 at position 4 (TAAGCT) is protected by Bicoid homeodomain [20].
  • Using transient transfection, we overexpressed green fluorescent protein-tagged versions of all three mammalian IP(3)K isoforms, including mutants with disrupted cellular localization or calmodulin regulation, and then imaged the Ca(2+) release stimulated by 100 mum histamine [21].

Physical interactions of bcd

  • Alteration of the arrangement of Bcd binding sites in the kni enhancer element reduces the role of the amino-terminal domain in cooperative DNA binding but increases the effectiveness of the self-inhibitory function [22].
  • We have recently shown that Bcd binds cooperatively to a hb enhancer element and proposed that cooperative DNA binding is facilitated by an interaction between Bcd molecules [23].
  • DSP1 interacts with bicoid for knirps enhancement [24].
  • We propose that Swa acts as an adaptor for the dynein complex and thereby enables dynein to transport bcd RNA along microtubules to their minus ends at the anterior pole of the oocyte [14].
  • Upon injection into the embryo, bcd transcripts specifically interact with staufen, and we have mapped the sequences required to three regions of the 3'UTR, each of which is predicted to form a long stem-loop [8].
  • The Bcd protein contains two functional domains [25] , [26], [27], a carboxy-terminal transcriptional activation domain, and an amino-terminal homeodo-main, which is necessary for DNA binding [28], [29], [30], [31].
  • It has been shown a strong cooperative effect for the binding of Bcd molecules to neighboring sites in the hb enhancer element [32], [30], [33], [34]

Enzymatic interactions of bcd


Co-localisations of bcd

  • Notably, we find that exu protein is colocalized with bcd mRNA during the early phase of localization, when bcd mRNA is positioned at the apical regions of the nurse cells [36].

Regulatory relationships of bcd

  • When active inappropriately at the anterior pole, nos can also block expression of the anterior determinant bicoid (bcd) [37].
  • Zygotic expression of hb is directly activated by the bcd gene product, leading to a subdivision of the embryo into an anterior half expressing zygotically provided hb protein and a posterior half that does not [38].
  • We demonstrate that the prototypical Puf protein Pumilio temporally regulates bicoid (bcd) mRNA translation via evolutionarily conserved Nanos response elements (NRE) in its 3'UTR [39].
  • In Drosophila S2 cells, the Bcd activity is increased by the co-transfection of plasmids expressing dCBP and reduced by double-stranded RNA-mediated interference against dCBP [40].
  • This suggests that bcd may act in the region-specific control of cad mRNA translation [41].

Other interactions of bcd

  • In contrast to the Bcd gradient, the hb expression pattern already includes the information about the scale of the embryo [42].
  • In vitro, kni protein competes with the homeodomain-containing bcd protein in binding to a 16-base pair target sequence [43].
  • Forming the posterior border of the stripe involves a delicate balance between limiting amounts of the bcd activator and the Kr repressor [12].
  • Phosphorylation of bicoid on MAP-kinase sites: contribution to its interaction with the torso pathway [44].
  • Phenotypically, embryos from transgenic mothers that harbor bcd NRE mutations exhibited dominant anterior patterning defects and we discovered similar head defects in embryos from pum(-) mothers [39].

Analytical, diagnostic and therapeutic context of bcd


  1. Heads or tails: host-parasite interactions in the Drosophila-Wolbachia system. Veneti, Z., Clark, M.E., Karr, T.L., Savakis, C., Bourtzis, K. Appl. Environ. Microbiol. (2004) [Pubmed]
  2. RNA loop-loop interactions as dynamic functional motifs. Brunel, C., Marquet, R., Romby, P., Ehresmann, C. Biochimie (2002) [Pubmed]
  3. RNA nanotechnology: engineering, assembly and applications in detection, gene delivery and therapy. Guo, P. Journal of nanoscience and nanotechnology. (2005) [Pubmed]
  4. Evaluation of the antibacterial spectrum of drosocin analogues. Bikker, F.J., Kaman-van Zanten, W.E., de Vries-van de Ruit, A.M., Voskamp-Visser, I., van Hooft, P.A., Mars-Groenendijk, R.H., de Visser, P.C., Noort, D. Chemical biology & drug design. (2006) [Pubmed]
  5. A new paradigm for translational control: inhibition via 5'-3' mRNA tethering by Bicoid and the eIF4E cognate 4EHP. Cho, P.F., Poulin, F., Cho-Park, Y.A., Cho-Park, I.B., Chicoine, J.D., Lasko, P., Sonenberg, N. Cell (2005) [Pubmed]
  6. In vivo analysis of Drosophila bicoid mRNA localization reveals a novel microtubule-dependent axis specification pathway. Cha, B.J., Koppetsch, B.S., Theurkauf, W.E. Cell (2001) [Pubmed]
  7. The Drosophila homolog of C. elegans PAR-1 organizes the oocyte cytoskeleton and directs oskar mRNA localization to the posterior pole. Shulman, J.M., Benton, R., St Johnston, D. Cell (2000) [Pubmed]
  8. Staufen protein associates with the 3'UTR of bicoid mRNA to form particles that move in a microtubule-dependent manner. Ferrandon, D., Elphick, L., Nüsslein-Volhard, C., St Johnston, D. Cell (1994) [Pubmed]
  9. Synergy between the hunchback and bicoid morphogens is required for anterior patterning in Drosophila. Simpson-Brose, M., Treisman, J., Desplan, C. Cell (1994) [Pubmed]
  10. Implications for bcd mRNA localization from spatial distribution of exu protein in Drosophila oogenesis. Wang, S., Hazelrigg, T. Nature (1994) [Pubmed]
  11. Mediation of Drosophila head development by gap-like segmentation genes. Cohen, S.M., Jürgens, G. Nature (1990) [Pubmed]
  12. Regulation of even-skipped stripe 2 in the Drosophila embryo. Small, S., Blair, A., Levine, M. EMBO J. (1992) [Pubmed]
  13. Bicoid cooperative DNA binding is critical for embryonic patterning in Drosophila. Lebrecht, D., Foehr, M., Smith, E., Lopes, F.J., Vanario-Alonso, C.E., Reinitz, J., Burz, D.S., Hanes, S.D. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  14. The molecular motor dynein is involved in targeting swallow and bicoid RNA to the anterior pole of Drosophila oocytes. Schnorrer, F., Bohmann, K., Nüsslein-Volhard, C. Nat. Cell Biol. (2000) [Pubmed]
  15. Persistence of Hunchback in the terminal region of the Drosophila blastoderm embryo impairs anterior development. Janody, F., Reischl, J., Dostatni, N. Development (2000) [Pubmed]
  16. Differential regulation of the two transcripts from the Drosophila gap segmentation gene hunchback. Schröder, C., Tautz, D., Seifert, E., Jäckle, H. EMBO J. (1988) [Pubmed]
  17. Mutations that perturb poly(A)-dependent maternal mRNA activation block the initiation of development. Lieberfarb, M.E., Chu, T., Wreden, C., Theurkauf, W., Gergen, J.P., Strickland, S. Development (1996) [Pubmed]
  18. The solution structure of the native K50 Bicoid homeodomain bound to the consensus TAATCC DNA-binding site. Baird-Titus, J.M., Clark-Baldwin, K., Dave, V., Caperelli, C.A., Ma, J., Rance, M. J. Mol. Biol. (2006) [Pubmed]
  19. Small circular DNA in Drosophila melanogaster. Stanfield, S., Helinski, D.R. Cell (1976) [Pubmed]
  20. Reprogrammable recognition codes in bicoid homeodomain-DNA interaction. Dave, V., Zhao, C., Yang, F., Tung, C.S., Ma, J. Mol. Cell. Biol. (2000) [Pubmed]
  21. Regulation of inositol 1,4,5-trisphosphate 3-kinases by calcium and localization in cells. Lloyd-Burton, S.M., Yu, J.C., Irvine, R.F., Schell, M.J. J. Biol. Chem. (2007) [Pubmed]
  22. Enhancer sequences influence the role of the amino-terminal domain of bicoid in transcription. Fu, D., Zhao, C., Ma, J. Mol. Cell. Biol. (2003) [Pubmed]
  23. Sequences outside the homeodomain of bicoid are required for protein-protein interaction. Yuan, D., Ma, X., Ma, J. J. Biol. Chem. (1996) [Pubmed]
  24. DSP1 interacts with bicoid for knirps enhancement. Daulny, A., Rappailles, A., Landemarre, L., Locker, D., Decoville, M. Genesis (2003) [Pubmed]
  25. The role of localization of bicoid RNA in organizing the anterior pattern of the Drosophila embryo. Berleth, T., Burri, M., Thoma, G., Bopp, D., Richstein, S., Frigerio, G., Noll, M., Nüsslein-Volhard, C. EMBO. J. (1988) [Pubmed]
  26. The bicoid protein determines position in the Drosophila embryo in a concentration-dependent manner. Driever, W., Nüsslein-Volhard, C. Cell. (1988) [Pubmed]
  27. The gradient morphogen bicoid is a concentration-dependent transcriptional activator. Struhl, G., Struhl, K., Macdonald, P.M. Cell. (1989) [Pubmed]
  28. Target selectivity of bicoid is dependent on nonconsensus site recognition and protein-protein interaction. Zhao, C., Dave, V., Yang, F., Scarborough, T., Ma, J. Mol. Cell. Biol. (2000) [Pubmed]
  29. Reprogrammable recognition codes in bicoid homeodomain-DNA interaction. Dave, V., Zhao, C., Yang, F., Tung, C.S., Ma, J. Mol. Cell. Biol. (2000) [Pubmed]
  30. Sequences outside the homeodomain of bicoid are required for protein-protein interaction. Yuan, D., Ma, X., Ma, J. J. Biol. Chem. (1996) [Pubmed]
  31. Aromatic amino acids are critical for stability of the bicoid homeodomain. Subramaniam, V., Jovin, T.M., Rivera-Pomar, R.V. J. Biol. Chem. (2001) [Pubmed]
  32. The Drosophila morphogenetic protein Bicoid binds DNA cooperatively. Ma, X., Yuan, D., Diepold, K., Scarborough, T., Ma, J. Development. (1996) [Pubmed]
  33. Cooperative DNA-binding by Bicoid provides a mechanism for threshold-dependent gene activation in the Drosophila embryo. Burz, D.S., Rivera-Pomar, R., Jäckle, H., Hanes, S.D. EMBO. J. (1998) [Pubmed]
  34. Isolation of mutations that disrupt cooperative DNA binding by the Drosophila bicoid protein. Burz, D.S., Hanes, S.D. J. Mol. Biol. (2001) [Pubmed]
  35. Par-1 regulates bicoid mRNA localisation by phosphorylating Exuperantia. Riechmann, V., Ephrussi, A. Development (2004) [Pubmed]
  36. Protein encoded by the exuperantia gene is concentrated at sites of bicoid mRNA accumulation in Drosophila nurse cells but not in oocytes or embryos. Macdonald, P.M., Luk, S.K., Kilpatrick, M. Genes Dev. (1991) [Pubmed]
  37. RNA regulatory elements mediate control of Drosophila body pattern by the posterior morphogen nanos. Wharton, R.P., Struhl, G. Cell (1991) [Pubmed]
  38. A morphogenetic gradient of hunchback protein organizes the expression of the gap genes Krüppel and knirps in the early Drosophila embryo. Hülskamp, M., Pfeifle, C., Tautz, D. Nature (1990) [Pubmed]
  39. An anterior function for the Drosophila posterior determinant Pumilio. Gamberi, C., Peterson, D.S., He, L., Gottlieb, E. Development (2002) [Pubmed]
  40. The co-activator CREB-binding protein participates in enhancer-dependent activities of bicoid. Fu, D., Wen, Y., Ma, J. J. Biol. Chem. (2004) [Pubmed]
  41. RNA binding and translational suppression by bicoid. Rivera-Pomar, R., Niessing, D., Schmidt-Ott, U., Gehring, W.J., Jäckle, H. Nature (1996) [Pubmed]
  42. Establishment of developmental precision and proportions in the early Drosophila embryo. Houchmandzadeh, B., Wieschaus, E., Leibler, S. Nature (2002) [Pubmed]
  43. Competition for overlapping sites in the regulatory region of the Drosophila gene Krüppel. Hoch, M., Gerwin, N., Taubert, H., Jäckle, H. Science (1992) [Pubmed]
  44. Phosphorylation of bicoid on MAP-kinase sites: contribution to its interaction with the torso pathway. Janody, F., Sturny, R., Catala, F., Desplan, C., Dostatni, N. Development (2000) [Pubmed]
  45. The role of localization of bicoid RNA in organizing the anterior pattern of the Drosophila embryo. Berleth, T., Burri, M., Thoma, G., Bopp, D., Richstein, S., Frigerio, G., Noll, M., Nüsslein-Volhard, C. EMBO J. (1988) [Pubmed]
  46. Targeting gene expression to the head: the Drosophila orthodenticle gene is a direct target of the Bicoid morphogen. Gao, Q., Finkelstein, R. Development (1998) [Pubmed]
  47. Identification of drosophila bicoid-interacting proteins using a custom two-hybrid selection. Zhu, W., Hanes, S.D. Gene (2000) [Pubmed]
  48. Functional colocalization of ribozymes and target mRNAs in Drosophila oocytes. Lee, N.S., Sun, B., Williamson, R., Gunkel, N., Salvaterra, P.M., Rossi, J.J. FASEB J. (2001) [Pubmed]
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