Retinoic acid regulation of the somitogenesis clock

Retinoic acid (RA) is a signaling molecule synthesized from vitamin A that controls gene expression at the transcriptional level by functioning as a ligand for nuclear RA receptors. RA plays an essential role during embryonic development in higher animals by regulating key genes involved in pattern formation. RA is required for induction of several Hox genes involved in patterning of the hindbrain and spinal cord as neuroectoderm emerges from the primitive streak. Recent findings indicate that RA is also required to ensure bilaterally symmetrical generation of left and right somites as presomitic mesoderm emerges from the primitive streak. RA may control somitogenesis through its ability to repress posterior ectodermal expression of fibroblast growth factor-8 (Fgf8) for a short period of time during the late primitive streak stage when the somitogenesis clock initiates. During this tight temporal window, RA is required to limit Fgf8 expression to the most posterior ectoderm (epiblast), thus preventing ectopic Fgf8 expression in more anterior ectoderm including the node ectoderm and neuroectoderm. Although Fgf8 is required for the node to impart left-right asymmetry on specific tissues (heart, visceral organs, etc.), excess Fgf8 signaling following a loss of RA may stimulate the node to generate asymmetry also in presomitic mesoderm, leading to left-right asymmetry in the somitogenesis clock. These findings suggest that human vertebral birth defects such as scoliosis, an abnormal left-right bending of the vertebral column, may be caused by a defect in RA signaling during somitogenesis.