Retinoid signalling in the development of the central nervous system

Key Points Vitamin A is an essential component of the diet; in its absence, animals show characteristic changes, including keratinization of epithelia, decreased immune function, anaemia and blindness. Dietary deficiency during pregnancy also causes congenital malformations in the embryonic central nervous system (CNS). Retinoic acid (RA) is the most biologically active member of the retinoids — a family of molecules that are derived from vitamin A. RA is highly teratogenic when administered in excess to pregnant mammals, and it has been shown to cause patterning defects in the CNS. The primary neurons in fish and amphibians coordinate escape movements, and their numbers are regulated by RA. In addition to regulating the genes that control neuronal differentiation, RA switches on genes that pattern the neural plate along the anteroposterior (AP) axis. Initial experiments implied that it acts throughout the AP extent of the neural tube, but subsequent experiments have focused on a more localized role in the hindbrain and anterior spinal cord. There are two theories to explain how RA organizes AP patterning. There could be a head-to-tail gradient, with a high point at the posterior end, or there could be a localized source of RA at the posterior end of the hindbrain. The existence of a gradient has proved difficult to demonstrate, and recent findings seem to point towards the latter model. RA is also required for the patterning of neuronal populations along the dorsoventral axis of the neural tube. It seems to suppress ventral neuronal genes and to induce dorsal genes, allowing the generation of interneurons in the centre of the spinal cord. In addition, RA is required for the specification of lateral motor column neurons. As RA is an essential component of the adult diet, it is likely that RA signalling also occurs in the adult. The failure of any component of the RA signalling pathway would be expected to cause a malfunction in the neurons concerned. Indeed, defects in RA signalling have been implicated in several neurological diseases, including movement disorders, schizophrenia and motor neuron disease. Retinoids — a family of molecules that are derived from vitamin A — have been implicated in many developmental processes. In the embryonic vertebrate central nervous system (CNS), retinoic acid (RA) has a role in patterning both the anteroposterior and dorsoventral axes. Initially, RA was thought to be involved in generating the entire anteroposterior ext