Developmental Biology

Small molecules are powerful tools for studying developmental biology because they provide timing and dosage control over developmental pathways that is difficult to achieve with genetic mutations. Unfortunately, only a handful of developmental pathways can currently be targeted with small molecules. We are discovering novel chemical modifiers of developmental pathways by exposing zebrafish embryos to libraries of structurally diverse small molecules and identifying those that induce specific developmental defects. Using screens of this type, we have discovered dozens of compounds that cause specific defects in hematopoesis, cardiac physiology, embryonic patterning, pigmentation, and morphogenesis of the heart, brain, ear, and eye and germ cell lineage. Examples include:

Dorsomorphin

One notable lab success in recent years has been the discovery of dorsomorphin and related BMP receptor antagonists. These small molecules were discovered during a zebrafish screen for compounds that alter development of the embryonic dorsal-ventral axis. As the first compounds to antagonize BMP signaling, the molecules have become powerful tools for studying BMP functions, and the molecules have already been used in hundreds of other studies around the world. In addition, the compounds have proven to be effective in treating animal models of BMP-related disorders, including heterotopic ossification and anemia. The compounds are currently in late stages of preclinical development.

Yu et al, Nat Chem Biol. (2008) 4:33-41.
Yu et al, Nat. Med., (2008) 14:1363-9.

dorsomorphindorso

Gridlock suppressors

Zebrafish gridlock mutants exhibit a dysmorphogenesis of the aorta that prevents circulation to the trunk and tail and is a model of human coarctation of the aorta. Gridlock mutants were exposed to thousands of compounds from a diverse small molecule library. Several compounds were identified that completely restore gridlock mutants to normal without causing additional developmental defects. The “gridlock suppressors” identified have revealed fundamental insights into artery formation, and the compounds appear to be effective in promoting new artery formation in mouse models of ischemia.

Peterson et al, Nat Biotech. (2004) 22:595-9.
Hong et al, Curr Biol. (2006) 16:1366-72.
Ren et al, J Clin Invest (2010) 120:1217-28.

gridlock1

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