tretinoin and Situs-Inversus

Retinoic acid, the biologically active form of vitamin A, is a critical player in normal development. The concentration of retinoic acid is highly regulated by the embryo to prevent either a deficit or an excess of this molecule, conditions that have been shown to produce cardiac defects that vary depending on the severity and the timing of the insult. The vast majority of these defects are associated with the valves or the membranous septa of the heart, suggesting a problem with the formation of the cardiac mesenchyme from both within and outside the heart. While the exact role of retinoic acid in cardiac development is not known, it is believed that retinoic acid influences development by up- or down-regulating cardiac specific genes. This review briefly discusses the role of cardiac mesenchyme and cardiac neural crest in septation of the heart. This is followed by a discussion of vitamin A metabolism and the cardiac defects associated with abnormal levels of retinoic acid. Finally, a mechanism is proposed concerning the ways abnormal levels of retinoic acid lead to similar cardiac defects by disrupting the production of the extracellular matrix.

Topics: Animals; Extracellular Matrix; Heart; Heart Defects, Congenital; Humans; Mesoderm; Neural Crest; Situs Inversus; Tretinoin; Vitamin A

To decipher genes that are important in the determination of laterality, we compared two-dimensional protein gels from wild-type C57BL/6J mice and C57BL/6J mice that carried the iv mutation, which confers random determination of visceral situs. To span the time period(s) during which laterality determination occurs, we compared computer-analyzed two-dimensional protein gels from wild-type mouse embryos and iv/iv mouse embryos at 7.5, 8.0, and 8.5 days post-coitum. One polypeptide that was expressed only on day 8.0 of development and only in wild-type embryos represents a particular candidate for determination of laterality. Day 8.5 postcoitum represents the earliest time in murine development that laterality is manifest. Two-dimensional gels were compared from 8.5 day embryos that were C57BL/6J wild-type, C57BL/6J iv/iv, or C57BL/6J wild-type and exposed to the teratogen retinoic acid late on day 7. Reproducible alterations of protein synthesis were observed in both the iv genocopy and retinoic acid phenocopy, yielding abnormal laterality determination. The intersection of these peptide changes identifies a protein likely to play a role in the determination of laterality.

Topics: Animals; Electrophoresis, Gel, Two-Dimensional; Embryonic and Fetal Development; Functional Laterality; Image Processing, Computer-Assisted; Mice; Mice, Inbred C57BL; Mutation; Protein Biosynthesis; Proteins; Situs Inversus; Tretinoin