| Retinoic acid (RA), an active derivative of vitamin A (retinol), is required for embryogenesis and homeostasis. While the development of many systems depends on RA signaling through nuclear receptors, RA activity is excluded from several tissues that express the RA-catabolizing cytochrome P450 Cyp26A1, such as the hindbrain and tail bud. In this thesis, I characterize the function of mouse CYP26A1 in several F9 embryonal carcinoma cell-line derivatives and show that loss of CYP26A1 activity is embryonic lethal. Our work demonstrates that retinoic acid-receptor gamma (RARγ) and retinoid X-receptor alpha (RXRα) are required for mediating both RA-inducible Cyp26A1 expression and RA metabolism in the F9 cell line. Moreover, we show that Cyp26A1-null mutant animals, which exhibit caudal regression, resemble wild-type animals exposed to toxic doses of RA during late gastrulation. Previous reports have shown that mice lacking RARγ are resistant to the teratogenic effects of RA on caudal development. Here we report that loss of RARγ function rescues Cyp26A1 mutants from embryonic lethality by restoring WNT3A and FGF8 signaling activities in the tail bud of Cyp26A1-RARγ double mutant animals. Thus, in addition to characterizing the biological function of CYP26A1 during late gastrulation and tail bud development, we also show that it is possible to suppress the lethal effects of one null mutation by introducing another, a phenomenon as yet rarely observed in mouse. |
