Integrating retinoic acid signaling with brain function.

The vitamin A derivative retinoic acid (RA) regulates the transcription of about a 6th of the human genome. Compelling evidence indicates a role of RA in cognitive activities, but its integration with the molecular mechanisms of higher brain functions is not known. Here we describe the properties of RA signaling in the mouse, which point to unknown means through which RA actions are modified and reinforced at selected brain sites. The locations of RA signaling for the developing dorsal forebrain undergo slow, gradual changes over the life cycle except for two brief periods of accelerated shifts, which coincide with periods of enhanced developmental vulnerability. In the functional cerebral cortex, RA signaling delineates regions with immature, plastic neuronal characteristics, within which the expression of hundreds of genes is differentially regulated. Many of these are involved in neuronal ligand-receptor interactions and signaling cascades for activity dependent gene expression. We propose that RA functions in the brain by contributing topographical information and life cycle changes to combinatorial transcriptional mechanisms and that in the postnatal cortex RA signaling designates domains of modifiable neuronal circuitry.