Skip to main content

Thank you for visiting 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.

Chemical suppression of a genetic mutation in a zebrafish model of aortic coarctation


Conventional drug discovery approaches require a priori selection of an appropriate molecular target, but it is often not obvious which biological pathways must be targeted to reverse a disease phenotype1,2. Phenotype-based screens offer the potential to identify pathways and potential therapies that influence disease processes. The zebrafish mutation gridlock (grl, affecting the gene hey2) disrupts aortic blood flow in a region and physiological manner akin to aortic coarctation in humans3,4,5. Here we use a whole-organism, phenotype-based, small-molecule screen to discover a class of compounds that suppress the coarctation phenotype and permit survival to adulthood. These compounds function during the specification and migration of angioblasts. They act to upregulate expression of vascular endothelial growth factor (VEGF), and the activation of the VEGF pathway is sufficient to suppress the gridlock phenotype. Thus, organism-based screens allow the discovery of small molecules that ameliorate complex dysmorphic syndromes even without targeting the affected gene directly.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Chemical rescue of a genetic cardiovascular defect.
Figure 2: Chemical suppressors of gridlock act before aorta formation and upregulate VEGF expression.
Figure 3: VEGF cDNA injection suppresses the gridlock mutation.
Figure 4: GS4012 promotes endothelial cell tubule formation.


  1. 1

    Crews, C.M. & Splittgerber, U. Chemical genetics: exploring and controlling cellular processes with chemical probes. Trends Biochem. Sci. 24, 317–320 (1999).

    CAS  Article  Google Scholar 

  2. 2

    Schreiber, S.L. Target-oriented and diversity-oriented organic synthesis in drug discovery. Science 287, 1964–1969 (2000).

    CAS  Article  Google Scholar 

  3. 3

    Zhong, T.P., Rosenberg, M., Mohideen, M.A., Weinstein, B. & Fishman, M.C. gridlock, an HLH gene required for assembly of the aorta in zebrafish. Science 287, 1820–1824 (2000).

    CAS  Article  Google Scholar 

  4. 4

    Weinstein, B.M., Stemple, D.L., Driever, W. & Fishman, M.C. Gridlock, a localized heritable vascular patterning defect in the zebrafish. Nat. Med. 1, 1143–1147 (1995).

    CAS  Article  Google Scholar 

  5. 5

    Towbin, J.A. & McQuinn, T.C. Gridlock; a model for coarctation of the aorta? Nat. Med. 1, 1141–1142 (1995).

    CAS  Article  Google Scholar 

  6. 6

    St. Johnston, D. The art and design of genetic screens: Drosophila melanogaster. Nat. Rev. Genet. 3, 176–188 (2002).

    CAS  Article  Google Scholar 

  7. 7

    Sakata, Y. et al. Ventricular septal defect and cardiomyopathy in mice lacking the transcription factor CHF1/Hey2. Proc. Natl. Acad. Sci. USA 99, 16197–16202 (2002).

    CAS  Article  Google Scholar 

  8. 8

    Donovan, J., Kordylewska, A., Jan, Y.N. & Utset, M.F. Tetralogy of fallot and other congenital heart defects in hey2 mutant mice. Curr. Biol. 12, 1605–1610 (2002).

    CAS  Article  Google Scholar 

  9. 9

    Gessler, M. et al. Mouse gridlock: no aortic coarctation or deficiency, but fatal cardiac defects in hey2−/− mice. Curr. Biol. 183, 37–48 (1997).

    Google Scholar 

  10. 10

    Eriksson, J. & Lofberg, J. Development of the hypochord and dorsal aorta in the zebrafish embryo (Danio rerio). J. Morphol. 244, 167–176 (2000).

    CAS  Article  Google Scholar 

  11. 11

    Fouquet, B., Weinstein, B.M., Serluca, F.C. & Fishman, M.C. Vessel patterning in the embryo of the zebrafish: guidance by notochord. Dev. Biol. 183, 37–48 (1997).

    CAS  Article  Google Scholar 

  12. 12

    Cleaver, O. & Krieg, P.A. VEGF mediates angioblast migration during development of the dorsal aorta in Xenopus. Development 125, 3905–3914 (1998).

    CAS  PubMed  Google Scholar 

  13. 13

    Carmeliet, P. et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380, 435–439 (1996).

    CAS  Article  Google Scholar 

  14. 14

    Ferrara, N. et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380, 439–442 (1996).

    CAS  Article  Google Scholar 

  15. 15

    Stalmans, I. et al. VEGF: a modifier of the del22q11 (DiGeorge) syndrome? Nat. Med. 9, 173–182 (2003).

    CAS  Article  Google Scholar 

  16. 16

    Liang, D. et al. The role of vascular endothelial growth factor (VEGF) in vasculogenesis, angiogenesis, and hematopoiesis in zebrafish development. Mech. Dev. 108, 29–43 (2001).

    CAS  Article  Google Scholar 

  17. 17

    Zhong, T.P., Childs, S., Leu, J.P. & Fishman, M.C. Gridlock signaling pathway fashions the first embryonic artery. Nature 414, 216–220 (2001).

    CAS  Article  Google Scholar 

  18. 18

    Iso, T., Chung, G., Hamamori, Y. & Kedes, L. HERP1 is a cell type-specific primary target of Notch. J. Biol. Chem. 277, 6598–6607 (2002).

    CAS  Article  Google Scholar 

  19. 19

    Nakagawa, O. et al. Members of the HRT family of basic helix-loop-helix proteins act as transcriptional repressors downstream of Notch signaling. Proc. Natl. Acad. Sci. USA 97, 13655–13660 (2000).

    CAS  Article  Google Scholar 

  20. 20

    Lawson, N.D., Vogel, A.M. & Weinstein, B.M. Sonic hedgehog and vascular endothelial growth factor act upstream of the Notch pathway during arterial endothelial differentiation. Dev. Cell 3, 127–136 (2002).

    CAS  Article  Google Scholar 

  21. 21

    Ash, J.D. & Overbeek, P.A. Lens-specific VEGF-A expression induces angioblast migration and proliferation and stimulates angiogenic remodeling. Dev. Biol. 223, 383–398 (2000).

    CAS  Article  Google Scholar 

  22. 22

    Shin, J.T. & Fishman, M.C. From Zebrafish to human: modular medical models. Annu. Rev. Genomics Hum. Genet. 3, 311–340 (2002).

    CAS  Article  Google Scholar 

  23. 23

    Dooley, K. & Zon, L.I. Zebrafish: a model system for the study of human disease. Curr. Opin. Genet. Dev. 10, 252–256 (2000).

    CAS  Article  Google Scholar 

  24. 24

    Xu, X. et al. Cardiomyopathy in zebrafish due to mutation in an alternatively spliced exon of titin. Nat. Genet. 30, 205–209 (2002).

    CAS  Article  Google Scholar 

  25. 25

    Roman, B.L. et al. Disruption of acvrl1 increases endothelial cell number in zebrafish cranial vessels. Development 129, 3009–3019 (2002).

    CAS  PubMed  Google Scholar 

  26. 26

    Langheinrich, U. Zebrafish: a new model on the pharmaceutical catwalk. Bioessays 25, 904–912 (2003).

    CAS  Article  Google Scholar 

  27. 27

    Milan, D.J., Peterson, T.A., Ruskin, J.N., Peterson, R.T. & MacRae, C.A. Drugs that induce repolarization abnormalities cause bradycardia in zebrafish. Circulation 107, 1355–1358 (2003).

    Article  Google Scholar 

  28. 28

    Thomas, C.E., Ehrhardt, A. & Kay, M.A. Progress and problems with the use of viral vectors for gene therapy. Nat. Rev. Genet. 4, 346–358 (2003).

    CAS  Article  Google Scholar 

  29. 29

    Check, E. Cancer risk prompts US to curb gene therapy. Nature 422, 7 (2003).

    CAS  Article  Google Scholar 

  30. 30

    Wienholds, E., Schulte-Merker, S., Walderich, B. & Plasterk, R.H. Target-selected inactivation of the zebrafish rag1 gene. Science 297, 99–102 (2002).

    CAS  Article  Google Scholar 

Download references


This work was supported by grants from the National Institutes of Health, by the Ned Sahin Research Fund for Restoring Developmental Plasticity and by a sponsored research agreement with Novartis Institutes for Biomedical Research. S.Y.S. is a Physician-Postdoctoral Fellow and S.L.S. is an Investigator at the Howard Hughes Medical Institute. S.L.S. is also supported by a grant from the Donald W. Reynolds Cardiovascular Clinical Research Center (University of Texas Southwestern Medical Center).

Author information



Corresponding author

Correspondence to Randall T Peterson.

Ethics declarations

Competing interests

R.T.P. and C.A.M. receive research funding through a sponsored research agreement with Novartis Institutes for BioMedical Research.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Peterson, R., Shaw, S., Peterson, T. et al. Chemical suppression of a genetic mutation in a zebrafish model of aortic coarctation. Nat Biotechnol 22, 595–599 (2004).

Download citation


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