Hofsteen, P., Plavicki, J., Johnson, S.D., Peterson, R.E., and Heideman, W. (2013) Sox9b is Required for Epicardium Formation and Plays a Role in TCDD-induced Heart Malformation in Zebrafish. Molecular pharmacology. 84(3):353-60.
Activation of the transcription factor AHR by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) prevents the formation of the epicardium
and leads to severe heart malformations in developing zebrafish (Danio rerio). The downstream genes that cause heart malformation
are not known. Because TCDD causes craniofacial malformations in zebrafish by downregulating the sox9b gene, we hypothesized
that cardiotoxicity might also result from sox9b downregulation. We found that sox9b is expressed in the developing zebrafish
heart ventricle and that TCDD exposure markedly reduces this expression. Furthermore, we found that manipulation of sox9b
expression could phenocopy many but not all of the effects of TCDD at the heart. Loss of sox9b prevented the formation of
epicardium progenitors comprising the proepicardium on the pericardial wall, and prevented the formation and migration of
the epicardial layer around the heart. Zebrafish lacking sox9b showed pericardial edema, an elongated heart and reduced blood
circulation. Fish lacking sox9b failed to form valve cushions and leaflets. Sox9b is one of two mammalian Sox9 homologs,
sox9b and sox9a. Knock down of sox9a expression did not cause cardiac malformations, or defects in epicardium development.
We conclude that the decrease in sox9b expression in the heart caused by TCDD plays a role in many of the observed signs of
cardiotoxicity. We find that while sox9b is expressed in myocardial cells, it is not normally expressed in the affected epicardial
cells or progenitors. We therefore speculate that sox9b is involved in signals between the cardiomyocytes and the nascent