In this study, we used mouse embryos harboring null mutations in the genes coding for RALDH3, RARA, or RARG to unravel the possible interaction between atRA and TCDD during palate development and to reassess the etiology of TCDD-induced cleft palate.
To extend these observations, we quantified the mRNA levels of lacZ and endogenous atRA-target genes, including Crabp2 (cellular retinoic acid binding protein), Ram, and Rarg (Balmer and Blomhoff 2002).
RARA and RARG are the sole nuclear receptors driving atRA activity during craniofacial development (Lohnes et al.
Together, our findings that a) RARG, but not RARA, is mandatory for TCDD to induce cleft palate and b) RAR directly controls Ahr gene expression imply that the AHR-expressing cells at the origin of the malformation are necessarily distributed within the domain where RARG is operational.
Second, in vitro experiments indicate that TCDD induces expression of Rarg and Rrxa (Murphy et al.
mutants are resistant to TCDD-induced clefts, our study provides evidence that a functional, intact atRA signal originating from RALDH3, which is the sole atRA-synthesizing enzyme expressed in the palatal region and mediated by RARG in the facial mesenchyme, is required for TCDD to exert teratogenic effects on palate development.