Vitamin A and the Developing Eye
Vitamin A is an essential component of our food. Its biological role is due to two compounds, the aldehyde and the acid forms, to which it is converted within the body:
(1) Vitamin A aldehyde = retinaldehyde is the light-sensitive molecule on which vision is based. It converts the electromagnetic energy of light into a chemical and eventually an electrical signal, the energy form in which the brain processes information. Lack of retinaldehyde causes blindness.
(2) Vitamin A acid = retinoic acid is necessary for expression of many genes. It is of fundamental importance for the proper functioning of practically all organs in the adult, and it is even more essential for the developing embryo, in particular the emerging nervous system. While lack of retinoic acid leads to death, both of the adult and of the developing organism, too much retinoic acid is catastrophic mainly for the developing embryo. Accidental exposure of human embryos to retinoic acid, in the form of the acne drug Acutane®, causes severe malformations. The high vulnerability to external sources of retinoic acid reflects the critical dependence of the developing embryo to regulated, internally produced retinoic acid. Our work focuses on both aspects of vitamin A: on vision, and on the way by which retinoic acid, synthesized in the embryo, influences formation of the nervous system. This includes the mechanisms through which disturbances in retinoic acid cause malformations of the brain.
In pursuit of the mechanism by which the eye is formed in the early embryo, we identified the retinoic acid system as a critical component. Like the brain in general, the retina contains an address system for the formation of neuronal connections which is determined in two axes, an X- and a Y-axis, very early in the development of the embryo. We find that asymmetrical retinoic acid synthesis represents both the initial determination event for one of these retinal axes, as well as the mechanism for the lasting cellular memory of the axial orientation. Our recent work shows that the retinoic acid system divides the developing vertebrate retina into three distinct spatial domains, akin to the subdivisions in the developing insect eye disc. This provides evidence that the similarities between invertebrate and vertebrate eye development reach beyond single molecules to complex spatial patterning principles.
Our analyses of retinoic acid synthesis in the postnatal retina reveal an unexpected phenomenon that links the two vitamin A roles mentioned above. Some of the light-exposed visual chromophore retinaldehyde (the molecule on which vision is based) is converted to retinoic acid. This provides a mechanism through which light can directly influence gene expression in the eye. We have shown that retinoic acid administered in the dark mimics the effect of light for some proteins expressed in the eye. Light-induced retinoic acid synthesis can explain why 1) retinoic-acid activated transcription has evolved only rather recently, at the transition from invertebrates to vertebrates, and 2) why it plays such a central role in the vertebrate eye. Only in the vertebrate, but not in the invertebrate visual cycle does light generate free retinaldehyde (all-trans). Our observations indicate that the retinoic acid system originated in the eye, and that it represents a novel layer of control imposed over more ancient molecular systems.