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Gene Review

bnl  -  branchless

Drosophila melanogaster

Synonyms: BNL, Bnl, CG4608, DFGF, DmBnl, ...
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Disease relevance of bnl


High impact information on bnl

  • Male-specific deployment of FGF signaling is controlled by the sex determination regulatory gene doublesex [3].
  • We provide evidence that the critical signal is Branchless (Bnl) FGF, the same growth factor that patterns the major branches during embryogenesis [4].
  • sprouty encodes a novel antagonist of FGF signaling that patterns apical branching of the Drosophila airways [5].
  • In wild-type embryos, the Branchless FGF induces secondary branching by activating the Breathless FGF receptor near the tips of growing primary branches [5].
  • Generalized misexpression activates later programs of tracheal gene expression and branching, resulting in massive networks of branches. bnl encodes a homolog of mammalian fibroblast growth factors (FGFs) and appears to function as a ligand for the breathless receptor tyrosine kinase, an FGF receptor homolog expressed on developing tracheal cells [6].

Biological context of bnl

  • Misexpression of the bnl gene results in specific tracheal phenotypes that lead to larval death [7].
  • At each stage of branching, the mechanisms controlling FGF expression and the downstream signal transduction pathway change, altering the pattern and structure of the branches that form [1].
  • Stripe provides cues synergizing with branchless to direct tracheal cell migration [8].
  • For example, fibroblast growth factor (FGF) signaling is essential, not only for fly trachea and mouse bronchial branching morphogenesis, but also for postnatal modeling and repair of alveoli [9].
  • In addition, FGF signaling appears to regulate a small (< 5%) population of putative alveolar stem/ progenitor cells that express telomerase and are relatively resistant to hyperoxic apoptosis [9].

Anatomical context of bnl

  • We characterised the transcriptional profiles of targeted over-expression of bnl in the embryonic trachea and of loss-of-function bnl(P1) mutant embryos [7].
  • The Drosophila fibroblast growth factor (FGF) receptors Heartless and Breathless are required for the morphogenesis of the mesoderm and the tracheal system [10].
  • It seems unlikely that activation of transcription targets is essential for cell migration and it is possible that FGF signalling may have a direct effect on the cytoskeleton independent of the activation of the mitogen-activated protein kinase cascade [10].
  • Bnl/FGF signaling affects the formation of dynamic filopodia, possibly controlling cytoskeletal activity and motility as such, and Dpp controls cellular functions allowing branch morphogenesis and outgrowth [11].
  • We show that only the initial step of spreading, specifically the establishment of contact between the ectoderm and the mesoderm, depends upon FGF signalling, and that unlike the role of FGF signalling in the differentiation of heart precursors this function cannot be replaced by other receptor tyrosine kinases [12].

Associations of bnl with chemical compounds

  • Biochemical studies have shown that heparan sulfate glycosaminoglycans are involved in signaling by fibroblast growth factor receptors, but evidence for such a requirement in an intact organism has not been available [13].
  • Our screen also revealed that loss-of-function in laminin and integrin components results in both MADs and EMEs, the latter of which are suppressed by hyperactive FGF signaling [14].
  • Sequence analyses and comparative modeling of fly and worm fibroblast growth factor receptors indicate that the determinants for FGF and heparin binding are retained in evolution [15].

Regulatory relationships of bnl

  • These studies support a model in which both the Dpp- and the FGF-signaling pathways control expression of knirps and knirps-related, thereby regulating cell migration during dorsal branch formation [16].
  • Grainy head controls apical membrane growth and tube elongation in response to Branchless/FGF signalling [17].
  • Here, we show that trol encodes the Drosophila homolog of Perlecan and regulates neuroblast division by modulating both FGF and Hh signaling [18].
  • A strong heartbroken allele also suppresses the effects of hyperactivated FGF but not EGF receptors [19].
  • The Drosophila Sprouty (SPRY) protein has been shown to inhibit the actions of epidermal growth factor and fibroblast growth factor [20].

Other interactions of bnl

  • At least two of the genes, sar1 and robo2, show a genetic interaction with a hypomorphic dof allele, suggesting that they participate in FGF-mediated morphogenetic events during embryogenesis [21].
  • In vivo imaging reveals different cellular functions for FGF and Dpp signaling in tracheal branching morphogenesis [11].
  • JNK activity is necessary and sufficient for axon extension, whereas the antagonistic Wnt and FGF signals act to balance the extension and retraction required for the generation of the precise wiring pattern [22].
  • In addition, we observed that a key determinant of bridge-cell specification, the transcription factor Hunchback, is also required for bnl expression [23].
  • We conclude that distinct cellular identity codes are generated by the combinatorial activities of Wg, Dpp, EGF, and FGF signals in the progressive determination of embryonic mesodermal cells [24].

Analytical, diagnostic and therapeutic context of bnl

  • Thus, we identified and confirmed by quantitative PCR 13 Bnl-dependent genes that are expressed in cells within and outside of the tracheal system [7].
  • Dissection of the DSRF regulatory region reveals that a single enhancer element, which is under the control of the fibroblast growth factor (FGF)-receptor signalling pathway, is sufficient to induce DSRF expression in the terminal tracheal cells [25].
  • In addition, receptor tyrosine kinases (RTKs), and FGF receptors in particular, have emerged as key mediators of cell migration in vivo, confirming the importance of molecules that were initially identified and studied in cell culture [26].


  1. Branching morphogenesis of the Drosophila tracheal system. Ghabrial, A., Luschnig, S., Metzstein, M.M., Krasnow, M.A. Annu. Rev. Cell Dev. Biol. (2003) [Pubmed]
  2. Lepidopteran ortholog of Drosophila breathless is a receptor for the baculovirus fibroblast growth factor. Katsuma, S., Daimon, T., Mita, K., Shimada, T. J. Virol. (2006) [Pubmed]
  3. Sex-specific deployment of FGF signaling in Drosophila recruits mesodermal cells into the male genital imaginal disc. Ahmad, S.M., Baker, B.S. Cell (2002) [Pubmed]
  4. Oxygen regulation of airway branching in Drosophila is mediated by branchless FGF. Jarecki, J., Johnson, E., Krasnow, M.A. Cell (1999) [Pubmed]
  5. sprouty encodes a novel antagonist of FGF signaling that patterns apical branching of the Drosophila airways. Hacohen, N., Kramer, S., Sutherland, D., Hiromi, Y., Krasnow, M.A. Cell (1998) [Pubmed]
  6. branchless encodes a Drosophila FGF homolog that controls tracheal cell migration and the pattern of branching. Sutherland, D., Samakovlis, C., Krasnow, M.A. Cell (1996) [Pubmed]
  7. Identification of FGF-dependent genes in the Drosophila tracheal system. Stahl, M., Schuh, R., Adryan, B. Gene Expr. Patterns (2007) [Pubmed]
  8. Stripe provides cues synergizing with branchless to direct tracheal cell migration. Dorfman, R., Shilo, B.Z., Volk, T. Dev. Biol. (2002) [Pubmed]
  9. Do lung remodeling, repair, and regeneration recapitulate respiratory ontogeny? Warburton, D., Tefft, D., Mailleux, A., Bellusci, S., Thiery, J.P., Zhao, J., Buckley, S., Shi, W., Driscoll, B. Am. J. Respir. Crit. Care Med. (2001) [Pubmed]
  10. Fibroblast growth factor receptor-dependent morphogenesis of the Drosophila mesoderm. Wilson, R., Leptin, M. Philos. Trans. R. Soc. Lond., B, Biol. Sci. (2000) [Pubmed]
  11. In vivo imaging reveals different cellular functions for FGF and Dpp signaling in tracheal branching morphogenesis. Ribeiro, C., Ebner, A., Affolter, M. Dev. Cell (2002) [Pubmed]
  12. FGF signalling and the mechanism of mesoderm spreading in Drosophila embryos. Wilson, R., Vogelsang, E., Leptin, M. Development (2005) [Pubmed]
  13. Heparan sulfate proteoglycans are essential for FGF receptor signaling during Drosophila embryonic development. Lin, X., Buff, E.M., Perrimon, N., Michelson, A.M. Development (1999) [Pubmed]
  14. FGF negatively regulates muscle membrane extension in Caenorhabditis elegans. Dixon, S.J., Alexander, M., Fernandes, R., Ricker, N., Roy, P.J. Development (2006) [Pubmed]
  15. Sequence analyses and comparative modeling of fly and worm fibroblast growth factor receptors indicate that the determinants for FGF and heparin binding are retained in evolution. Nagendra, H.G., Harrington, A.E., Harmer, N.J., Pellegrini, L., Blundell, T.L., Burke, D.F. FEBS Lett. (2001) [Pubmed]
  16. A molecular link between FGF and Dpp signaling in branch-specific migration of the Drosophila trachea. Myat, M.M., Lightfoot, H., Wang, P., Andrew, D.J. Dev. Biol. (2005) [Pubmed]
  17. Grainy head controls apical membrane growth and tube elongation in response to Branchless/FGF signalling. Hemphälä, J., Uv, A., Cantera, R., Bray, S., Samakovlis, C. Development (2003) [Pubmed]
  18. Drosophila perlecan modulates FGF and hedgehog signals to activate neural stem cell division. Park, Y., Rangel, C., Reynolds, M.M., Caldwell, M.C., Johns, M., Nayak, M., Welsh, C.J., McDermott, S., Datta, S. Dev. Biol. (2003) [Pubmed]
  19. Heartbroken is a specific downstream mediator of FGF receptor signalling in Drosophila. Michelson, A.M., Gisselbrecht, S., Buff, E., Skeath, J.B. Development (1998) [Pubmed]
  20. The C terminus of sprouty is important for modulation of cellular migration and proliferation. Yigzaw, Y., Cartin, L., Pierre, S., Scholich, K., Patel, T.B. J. Biol. Chem. (2001) [Pubmed]
  21. A screen for genes that influence fibroblast growth factor signal transduction in Drosophila. Zhu, M.Y., Wilson, R., Leptin, M. Genetics (2005) [Pubmed]
  22. A signaling network for patterning of neuronal connectivity in the Drosophila brain. Srahna, M., Leyssen, M., Choi, C.M., Fradkin, L.G., Noordermeer, J.N., Hassan, B.A. PLoS Biol. (2006) [Pubmed]
  23. The Drosophila Extradenticle and Homothorax selector proteins control branchless/FGF expression in mesodermal bridge-cells. Merabet, S., Ebner, A., Affolter, M. EMBO Rep. (2005) [Pubmed]
  24. Combinatorial signaling codes for the progressive determination of cell fates in the Drosophila embryonic mesoderm. Carmena, A., Gisselbrecht, S., Harrison, J., Jiménez, F., Michelson, A.M. Genes Dev. (1998) [Pubmed]
  25. Expression of the blistered/DSRF gene is controlled by different morphogens during Drosophila trachea and wing development. Nussbaumer, U., Halder, G., Groppe, J., Affolter, M., Montagne, J. Mech. Dev. (2000) [Pubmed]
  26. The genetics of cell migration in Drosophila melanogaster and Caenorhabditis elegans development. Montell, D.J. Development (1999) [Pubmed]
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