Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The transformation of the model organism: a decade of developmental genetics

Nature Genetics volume 33, pages 285–293 (2003)Cite this article

Abstract

The past decade has seen the development of powerful techniques to dissect the molecular processes that regulate development. New tools have been used to reveal the basis of cell polarity, morphogen gradients and regulation of signaling in developing animals. Cell biology and developmental biology have become closely intertwined, and many genes that had been thought of as regulators of general cell biological (housekeeping) functions have been shown to act as specific developmental regulators. Vertebrate developmental genetics is now flourishing, with forward and reverse genetics in both zebrafish and the mouse providing new dimensions to our understanding of development.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Cell and tissue polarity revealed by GFP fusions.
Figure 2: Stable activation of gene expression using the flp-out technique.
Figure 3: Induction of labeled clones of mutant cells using FRT-mediated somatic recombination.
Figure 4: Negative feedback loops restrict the spatial and temporal range of signaling molecules.
Figure 5: Covalent modification is one mechanism used to modulate the activity of proteins required for intercellular signaling.
Figure 6: Whole-mount in situ hybridization makes it easier to visualize the anatomy of the mouse embryo.
Figure 7: Identification of mutations in zebrafish.
Figure 8: Two strategies for forward genetics in the mouse identify new genes important in development.

References

  1. Wolpert, L. Do we understand development? Science 266, 571–572 (1994).

    Article  CAS  PubMed  Google Scholar 

  2. Chalfie, M., Tu, Y., Euskirchen, G., Ward, W.W. & Prasher, D.C. Green fluorescent protein as a marker for gene expression. Science 263, 802–805 (1994).

    Article  CAS  PubMed  Google Scholar 

  3. Guo, S. & Kemphues, K.J. Molecular genetics of asymmetric cleavage in the early Caenorhabditis elegans embryo. Curr. Opin. Genet. Dev. 6, 408–415 (1996).

    Article  CAS  PubMed  Google Scholar 

  4. Reese, K.J., Dunn, M.A., Waddle, J.A. & Seydoux, G. Asymmetric segregation of PIE-1 in C. elegans is mediated by two complementary mechanisms that act through separate PIE-1 protein domains. Mol. Cell. 6, 445–455 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Bilder, D. Cell polarity: squaring the circle. Curr. Biol. 11, R132–R135. (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Lu, B., Ackerman, L., Jan, L.Y. & Jan, Y.N. Modes of protein movement that lead to the asymmetric localization of partner of Numb during Drosophila neuroblast division. Mol. Cell 4, 883–891 (1999).

    Article  CAS  PubMed  Google Scholar 

  7. Suzuki, A. et al. Atypical protein kinase C is involved in the evolutionarily conserved par protein complex and plays a critical role in establishing epithelia-specific junctional structures. J. Cell Biol. 152, 1183–1196 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Strutt, D.I. Asymmetric localization of Frizzled and the establishment of cell polarity in the Drosophila wing. Mol. Cell 7, 367–375 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Tree, D.R., Shulman, J.M., Rousset, R., Scott, M.P., Gubb, D. & Axelrod, J.D. Prickle mediates feedback amplification to generate asymmetric planar cell polarity signaling. Cell 109, 371–381 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Struhl, G. & Basler, K. Organizing activity of wingless protein in Drosophila. Cell 72, 527–540 (1993).

    Article  CAS  PubMed  Google Scholar 

  11. Golic, K.G. & Lindquist, S. The FLP recombinase of yeast catalyzes site-specific recombination in the Drosophila genome. Cell 59, 499–509 (1989).

    Article  CAS  PubMed  Google Scholar 

  12. Brand, A.H. & Perrimon, N. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118, 401–415 (1993).

    CAS  PubMed  Google Scholar 

  13. Fischer, J.A, Giniger, E., Maniatis, T. & Ptashne, M. GAL4 activates transcription in Drosophila. Nature 332, 853–856 (1988).

    Article  CAS  PubMed  Google Scholar 

  14. Bellen, H.J., O'Kane, C.J., Wilson, C., Grossniklaus, U., Pearson, R.K. & Gehring, W.J. P-element–mediated enhancer detection: a versatile method to study development in Drosophila. Genes Dev. 3, 1288–1300 (1989).

    Article  CAS  PubMed  Google Scholar 

  15. Zecca, M., Basler, K. & Struhl, G. Sequential organizing activities of engrailed, hedgehog and decapentaplegic in the Drosophila wing. Development 121, 2265–2278 (1995).

    CAS  PubMed  Google Scholar 

  16. Zecca, M., Basler, K. & Struhl, G. Direct and long-range action of a wingless morphogen gradient. Cell 87, 833–844 (1996).

    Article  CAS  PubMed  Google Scholar 

  17. Nellen, D., Burke, R., Struhl, G. & Basler, K. Direct and long-range action of a DPP morphogen gradient. Cell 85, 357–368 (1996).

    Article  CAS  PubMed  Google Scholar 

  18. Strigini, M. & Cohen, S.M. Wingless gradient formation in the Drosophila wing. Curr. Biol. 10, 293–300 (2000).

    Article  CAS  PubMed  Google Scholar 

  19. Lander, A.D., Nie, Q. & Wan, F.Y. Do morphogen gradients arise by diffusion? Dev. Cell 2, 785–796 (2002).

    Article  CAS  PubMed  Google Scholar 

  20. Xu, T. & Rubin, G.M. Analysis of genetic mosaics in developing and adult Drosophila tissues. Development 117, 1223–1237 (1993).

    CAS  PubMed  Google Scholar 

  21. Pan, D. & Rubin, G.M. cAMP-dependent protein kinase and hedgehog act antagonistically in regulating decapentaplegic transcription in Drosophila imaginal discs. Cell 80, 543–552 (1995).

    Article  CAS  PubMed  Google Scholar 

  22. Jiang, J. & Struhl, G. Regulation of the Hedgehog and Wingless signalling pathways by the F-box/WD40-repeat protein Slimb. Nature 391, 493–496 (1998).

    Article  CAS  PubMed  Google Scholar 

  23. Simon, M.A., Bowtell, D.D., Dodson, G.S., Laverty, T.R. & Rubin, G.M. Ras1 and a putative guanine nucleotide exchange factor perform crucial steps in signaling by the Sevenless protein tyrosine kinase. Cell 67, 701–716 (1991).

    Article  CAS  PubMed  Google Scholar 

  24. Karim, F.D., Chang, H.C., Therrien, M., Wassarman, D.A., Laverty, T. & Rubin, G.M. A screen for genes that function downstream of Ras1 during Drosophila eye development. Genetics 143, 315–329 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Chen, Y. & Struhl, G. Dual roles for patched in sequestering and transducing Hedgehog. Cell 87, 553–563 (1996).

    Article  CAS  PubMed  Google Scholar 

  26. Freeman, M. Feedback control of intercellular signalling in development. Nature 408, 313–319 (2000).

    Article  CAS  PubMed  Google Scholar 

  27. Gerlitz, O. & Basler, K. Wingful, an extracellular feedback inhibitor of Wingless. Genes Dev. 16, 1055–1059 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ye, Y. & Fortini, M.E. Proteolysis and developmental signal transduction. Semin. Cell Dev. Biol. 11, 211–221 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. Lai, E.C. Protein degradation: four E3s for the Notch pathway. Curr. Biol. 12, R74–R78 (2002).

    Article  CAS  PubMed  Google Scholar 

  30. Moustakas, A., Souchelnytskyi, S. & Heldin, C.H. Related Smad regulation in TGF-β signal transduction. J. Cell. Sci. 114, 4359–4369 (2001).

    CAS  PubMed  Google Scholar 

  31. Maniatis, T. A ubiquitin ligase complex essential for the NF-κB, Wnt/Wingless, and Hedgehog signaling pathways. Genes Dev. 13, 505–510 (1999).

    Article  CAS  PubMed  Google Scholar 

  32. Dubois, L., Lecourtois, M., Alexandre, C., Hirst, E. & Vincent, J.P. Regulated endocytic routing modulates Wingless signaling in Drosophila embryos. Cell 105, 613–624 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Lee, J.R., Urban, S., Garvey, C.F. & Freeman, M. Regulated intracellular ligand transport and proteolysis control EGF signal activation in Drosophila. Cell 107, 161–171 (2001).

    Article  CAS  PubMed  Google Scholar 

  34. Sen, J., Goltz, J.S., Konsolaki, M., Schüpbach, T. & Stein, D. Windbeutel is required for function and correct subcellular localization of the Drosophila patterning protein Pipe. Development 127, 5541–5550 (2000).

    CAS  PubMed  Google Scholar 

  35. Sen, J., Goltz, J.S., Stevens, L. & Stein, D. Spatially restricted expression of pipe in the Drosophila egg chamber defines embryonic dorsal–ventral polarity. Cell 95, 471–481 (1998).

    Article  CAS  PubMed  Google Scholar 

  36. Tanaka, K., Kitagawa, Y. & Kadowaki, T. Drosophila segment polarity gene product porcupine stimulates the posttranslational N-glycosylation of Wingless in the endoplasmic reticulum. J. Biol. Chem. 277, 12816–12823 (2002).

    Article  CAS  PubMed  Google Scholar 

  37. Burke, R. et al. Dispatched, a novel sterol-sensing domain protein dedicated to the release of cholesterol-modified Hedgehog from signaling cells. Cell 99, 803–815 (1999).

    Article  CAS  PubMed  Google Scholar 

  38. Keleman, K. et al. Comm sorts Robo to control axon guidance at the Drosophila midline. Cell 110, 415–427 (2002).

    Article  CAS  PubMed  Google Scholar 

  39. Justice, N.J. & Jan, Y.N. Variations on the Notch pathway in neural development. Curr. Opin. Neurobiol. 12, 64–70 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Moloney, D.J. et al. Fringe is a glycosyltransferase that modifies Notch. Nature 406, 369–375 (2000).

    Article  CAS  PubMed  Google Scholar 

  41. Sisson, J.C., Ho, K.S., Suyama, K. & Scott, M.P. Costal2, a novel kinesin-related protein in the Hedgehog signaling pathway. Cell 90, 235–245 (1997).

    Article  CAS  PubMed  Google Scholar 

  42. Eggenschwiler, J.T., Espinoza, E. & Anderson, K.V. Rab23 is an essential negative regulator of the mouse Sonic hedgehog signalling pathway. Nature 412, 194–198 (2001).

    Article  CAS  PubMed  Google Scholar 

  43. Kmita, M., Fraudeau, N., Herault, Y. & Duboule, D. Serial deletions and duplications suggest a mechanism for the collinearity of Hoxd genes in limbs. Nature 420, 145–150 (2002).

    Article  CAS  PubMed  Google Scholar 

  44. Fuchs, E., Merrill, B.J., Jamora, C. & DasGupta, R. At the roots of a never-ending cycle. Dev. Cell. 1, 13–25 (2001).

    Article  CAS  PubMed  Google Scholar 

  45. Radtke, F. et al. Deficient T cell fate specification in mice with an induced inactivation of Notch1. Immunity 10, 547–558 (1999).

    Article  CAS  PubMed  Google Scholar 

  46. Rosen, B. & Beddington, R.S. Whole-mount in situ hybridization in the mouse embryo: gene expression in three dimensions. Trends Genet. 9, 162–167 (1993).

    Article  CAS  PubMed  Google Scholar 

  47. Beddington, R.S. Induction of a second neural axis by the mouse node. Development 12, 613–620 (1994).

    Google Scholar 

  48. Thomas, P. & Beddington, R. Anterior primitive endoderm may be responsible for patterning the anterior neural plate in the mouse embryo. Curr. Biol. 6, 1487–1496 (1996).

    Article  CAS  PubMed  Google Scholar 

  49. Heasman, J. Morpholino oligos: making sense of antisense? Dev. Biol. 243, 209–214 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Calegari, F., Haubensak, W., Yang, D., Huttner, W.B. & Buchholz, F. Tissue-specific RNA interference in postimplantation mouse embryos with endoribonuclease-prepared short interfering RNA. Proc. Natl. Acad. Sci. USA 99, 14236–14240 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Mellitzer, G., Hallonet, M., Chen, L. & Ang, S.L. Spatial and temporal 'knock down' of gene expression by electroporation of double-stranded RNA and morpholinos into early postimplantation mouse embryos. Mech. Dev. 118, 57–63 (2002).

    Article  CAS  PubMed  Google Scholar 

  52. Zhang, J., Talbot, W.S. & Schier, A.F. Positional cloning identifies zebrafish one-eyed pinhead as a permissive EGF-related ligand required during gastrulation. Cell 92, 241–251 (1998).

    Article  CAS  PubMed  Google Scholar 

  53. Kupperman, E., An, S., Osborne, N., Waldron, S. & Stainier, D.Y. A sphingosine-1-phosphate receptor regulates cell migration during vertebrate heart development. Nature 406, 192–195 (2000).

    Article  CAS  PubMed  Google Scholar 

  54. Walsh, E.C. & Stainier, D.Y. UDP-glucose dehydrogenase required for cardiac valve formation in zebrafish. Science 293, 1670–1673 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Cordes, S.P. & Barsh, G.S. The mouse segmentation gene kr encodes a novel basic domain-leucine zipper transcription factor. Cell 79, 1025–1034 (1994).

    Article  CAS  PubMed  Google Scholar 

  56. Shumacher, A., Faust, C. & Magnuson, T. Positional cloning of a global regulator of anterior–posterior patterning in mice. Nature 383, 250–253 (1996).

    Article  CAS  PubMed  Google Scholar 

  57. Kibar, Z, Voganm K.J., Groulx, N., Justice, M.J., Underhill, D.A. & Gros, P. Ltap, a mammalian homolog of Drosophila Strabismus/Van Gogh, is altered in the mouse neural tube mutant Loop-tail. Nat. Genet. 28, 251–255 (2001).

    Article  CAS  PubMed  Google Scholar 

  58. Hentges, K.E. et al. FRAP/mTOR is required for proliferation and patterning during embryonic development in the mouse. Proc. Natl. Acad. Sci. USA 98, 13796–13801 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Caspary, T. et al. Mouse Dispatched homolog1 is required for long-range but not juxtacrine Hh signaling. Curr. Biol. 12, 1628–1632 (2002).

    Article  CAS  PubMed  Google Scholar 

  60. Leighton, P.A. et al. Defining brain wiring patterns and mechanisms through gene trapping in mice. Nature 410, 174–179 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. Stanford, W.L., Cohn, J.B. & Cordes, S.P. Gene-trap mutagenesis: past, present and beyond. Nat. Rev. Genet. 2, 756–768 (2001).

    Article  CAS  PubMed  Google Scholar 

  62. Wallis, D. & Muenke, M. Mutations in holoprosencephaly. Hum. Mutat. 16, 99–108 (2000).

    Article  CAS  PubMed  Google Scholar 

  63. van de Wetering, M. et al. The β-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 111, 241–250 (2002).

    Article  CAS  PubMed  Google Scholar 

  64. Goodrich, L.V. & Scott, M.P. (1998) Hedgehog and patched in neural development and disease. Neuron 21, 1243–1257 (1998).

    Article  CAS  PubMed  Google Scholar 

  65. Anderson, K.V. Toll signaling pathways in the innate immune response. Curr. Opin. Immunol. 12, 13–19 (2000).

    Article  CAS  PubMed  Google Scholar 

  66. Selkoe, D.J. Presenilin, Notch, and the genesis and treatment of Alzheimer's disease. Proc. Natl. Acad. Sci. USA 98, 11039–11041 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Wolkow, C.A., Kimura, K.D., Lee, M.S. & Ruvkun, G. Regulation of C. elegans life-span by insulin-like signaling in the nervous system. Science 290, 147–150 (2000).

    Article  CAS  PubMed  Google Scholar 

  68. Fraser, A.G., Kamath, R.S., Zipperlen, P., Martinez-Campos, M., Sohrmann, M. & Ahringer, J. Functional genomic analysis of C. elegans chromosome I by systematic RNA interference. Nature 408, 325–330 (2000).

    Article  CAS  PubMed  Google Scholar 

  69. Gonczy, P. et al. Functional genomic analysis of cell division in C. elegans using RNAi of genes on chromosome III. Nature 408, 331–336 (2000).

    Article  CAS  PubMed  Google Scholar 

  70. Furlong, E.E., Andersen, E.C., Null, B., White, K.P. & Scott, M.P. Patterns of gene expression during Drosophila mesoderm development. Science 293, 1629–1633 (2001).

    Article  CAS  PubMed  Google Scholar 

  71. Hughes, C.L. & Kaufman, T.C. RNAi analysis of Deformed, proboscipedia and Sex combs reduced in the milkweed bug Oncopeltus fasciatus: novel roles for Hox genes in the hemipteran head. Development 127, 3683–3694 (2000).

    CAS  PubMed  Google Scholar 

  72. Plasterk, R.H., Izsvak, Z. & Ivics, Z. Resident aliens: the Tc1/mariner superfamily of transposable elements. Trends Genet. 15, 326–332 (1999).

    Article  CAS  PubMed  Google Scholar 

  73. Adler, P.N. Planar signaling and morphogenesis in Drosophila. Dev. Cell 2, 525–535 (2002).

    Article  CAS  PubMed  Google Scholar 

  74. Johnson, R.L., Grenier, J.K. & Scott, M.P. Patched overexpression alters wing disc size and pattern: transcriptional and post-transcriptional effects on hedgehog targets. Development 121, 4161–4170 (1995).

    CAS  PubMed  Google Scholar 

  75. Wilson, V., Rashbass, P. and Beddington, R.S.P. Chimeric analysis of T (Brachyury) gene function. Development 117, 1321–1331 (1993).

    CAS  PubMed  Google Scholar 

  76. Hamada, H., Meno, C., Watanabe, D. & Saijoh, Y. Establishment of vertebrate left–right asymmetry. Nat. Rev. Genet. 3, 103–113 (2002).

    Article  CAS  PubMed  Google Scholar 

  77. Pinson, K.I., Brennan, J., Monkley, S., Avery, B.J. & Skarnes, W.C. An LDL-receptor–related protein mediates Wnt signalling in mice. Nature 407, 535–538 (2000).

    Article  CAS  PubMed  Google Scholar 

  78. Kasarskis, A., Manova, K. & Anderson, K.V. A phenotype-based screen for ENU-induced embryonic lethal mutations in the mouse. Proc. Natl. Acad. Sci. USA 95, 7485–7490 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Developmental Biology Program, Sloan-Kettering Institute, New York, 10021, New York, USA

    Kathryn V. Anderson

  2. Department of Biomedical Science, Centre for Developmental Genetics, University of Sheffield, Sheffield, UK

    Philip W. Ingham

Authors
  1. Kathryn V. Anderson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Philip W. Ingham
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kathryn V. Anderson.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Anderson, K., Ingham, P. The transformation of the model organism: a decade of developmental genetics. Nat Genet 33 (Suppl 3), 285–293 (2003). https://doi.org/10.1038/ng1105

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1105

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing