Identification of a novel retinoid by small molecule screening with zebrafish embryos.
Small molecules have played an important role in delineating molecular pathways involved in embryonic development and disease pathology. The need for novel small molecule modulators of biological processes has driven a number of targeted screens on large diverse libraries. However, due to the specific focus of such screens, the majority of the bioactive potential of these libraries remains unharnessed. In order to identify a higher proportion of compounds with interesting biological activities, we screened a diverse synthetic library for compounds that perturb the development of any of the multiple organs in zebrafish embryos. We identified small molecules that affect the development of a variety of structures such as heart, vasculature, brain, and body-axis. We utilized the previously known role of retinoic acid in anterior-posterior (A-P) patterning to identify the target of DTAB, a compound that caused A-P axis shortening in the zebrafish embryo. We show that DTAB is a retinoid with selective activity towards retinoic acid receptors gamma and beta. Thus, conducting zebrafish developmental screens using small molecules will not only enable the identification of compounds with diverse biological activities in a large chemical library but may also facilitate the identification of the target pathways of these biologically active molecules.
Sachidanandan
Chetana
C
Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, United States of America.
Yeh
Jing-Ruey J
JR
Peterson
Quinn P
QP
Peterson
Randall T
RT
D062365:Aminobenzoates / Q000494:pharmacology*; D000818:Animals; D019521:Body Patterning; D002460:Cell Line; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D017403:In Situ Hybridization; D008954:Models, Biological; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D047488:Retinoid X Receptors / Q000378:metabolism; D012176:Retinoids / Q000378:metabolism*; D015398:Signal Transduction; D014212:Tretinoin / Q000378:metabolism; D014227:Triazines; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000378:metabolism; D062368:meta-Aminobenzoates; D000097768:Retinoic Acid Receptor gamma
D062365:Aminobenzoates; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D012176:Retinoids; D014212:Tretinoin; D014227:Triazines; D029961:Zebrafish Proteins; D062368:meta-Aminobenzoates; D000097768:Retinoic Acid Receptor gamma; C529372:3-((4,6-diphenoxy-1,3,5-triazin-2-yl)amino)benzoic acid; C082925:retinoic acid receptor beta