The vitamin A metabolite retinoic acid (RA) regulates the expression of a large number of proteins including many involved in neural development, function and plasticity. Both vitamin A deficiency and excess can be teratogenic for the developing brain. Previously we identified RA-synthesizing enzymes that determine local RA levels in the embryo. High expression of these enzymes in the developing eye and face cause extremely high RA concentrations here. In the brain, by comparison, overall RA levels are very low. Our working hypotheses are: (1) that the distribution of RA in the developing brain is very uneven, because a few sites of very high RA synthesis give rise to long-range RA diffusion patterns; (2) that this uneven distribution is necessary for normal brain development; it could explain the vulnerability of the brain to exogenous RA. We propose to identify, from where RA for the brain originates, and where and at what times it is likely to act. Our hypothesis is that the developing central visual system is supplied with RA by diffusion from several spatially restricted sources of RALDH expression: the eye and face, the ganglionic eminence, the optic axons, and the meninges. RA responses will be detected in a transgenic mouse strain whose tissues respond to RA with expression of a reporter gene. To probe for developmental processes during which RA is required, we will perturb its levels in pregnant mice. We propose to test the hypothesis that specific RA actions in the rostral brain are limited to restricted developmental times and that they follow the neuromeric organization, similar to the known RA effects on the developing rhombencephalon. An understanding of how RA acts on the central visual system will allow insight into what symptoms to expect in retinoid malfunctions.
| Luo, Tuanlian; Wagner, Elisabeth; Grun, Felix et al. (2004) Retinoic acid signaling in the brain marks formation of optic projections, maturation of the dorsal telencephalon, and function of limbic sites. J Comp Neurol 470:297-316 |
| Luo, Tuanlian; Wagner, Elisabeth; Crandall, James E et al. (2004) A retinoic-acid critical period in the early postnatal mouse brain. Biol Psychiatry 56:971-80 |
