Vitamin-A actions in the developing retina and forebrain
Ursula Dräger
A sufficient supply of vitamin A (= retinol) in the food is required for two functions: (1) the retinol derivative retinaldehyde forms the light-sensitive receptor in the retina necessary for vision, and (2) the derivative retinoic acid regulates gene transcription. Retinoic acid influences the expression of a large number of proteins throughout the body, including many involved in development, function and plasticity. Both too much and too little vitamin A can be harmful at any stage of life, but early embryonic development is by far the most vulnerable time, when both vitamin-A perturbations can cause lasting malformations. Nutritional vitamin-A deficiency is frequent worldwide; its best-known symptoms are disturbances of the eye: mild vitamin-A deficiency during embryonic development can cause ocular deformities, and in the functional eye impaired night vision is an early symptom. A more pervasive consequence of vitamin-A deficiency is an increase in the susceptibility to infectious diseases, because the function of the immune system is vitamin-A dependent. Moreover, also under normal nutritional conditions will activation of a immune response lead to a severe reduction in the circulating retinol levels that are available to the brain, but this reduction is temporary, limited to the duration of the infection or injury.
Practically all recognized vitamin-A related malformations are initiated during very early embryonic development and they are often lethal. We are studying later stages of retina and forebrain development in mice, in order to identify which steps in neuronal maturation normally involve retinoic acid and which could be vulnerable to temporary vitamin-A imbalances. We find distinct retinoic-acid dependent processes during later development, and disturbances in vitamin-A levels at that stage tend not to be lethal, but they can cause lasting functional abnormalities in the mice. During later development of the retina, we observe that the region for higher-acuity vision is transiently delineated by several retinoic-acid synthesizing and degrading enzymes. This raises the possibility that the maturation of retinal specializations generally depends on local borders between retinoic-acid rich and retinoic-acid free regions. In the cerebral cortex we observe that retinoic acid influences the maturation of subpopulations of inhibitory interneurons. These are the same interneuron classes that have been identified as substrate for functional plasticity and that are known to be impaired in several poorly understood human brain diseases. The high genetic complexity of the retinoid system and its dependence on a regulated nutritional vitamin-A supply make it possible that disturbances in retinoic-acid regulated gene expression might play a role in some complex human diseases, in which both genetic and environmental etiologies are implicated.
Recent publications:
Luo, T., Wagner, E., Grün, F., and Dräger, U.C. (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
Sakai, Y., Luo, T., McCaffery, P., Hamada, H., and Dräger, U.C. (2004). CYP26A1 and CYP26C1 cooperate in degrading retinoic acid within the equatorial retina during later eye development. Dev.Biol., 276: 143-157.
Luo, T., Wagner, E., Crandall, J.E., and Dräger, U.C. (2004). A retinoic-acid critical period in the early postnatal mouse brain. Biol.Psychiatry 56: 971-980.