Retinoic Acid, a Regeneration-Inducing Molecule in Mammals

M. Maden

MRC Centre for Developmental Neurobiology
King’s College London
Guy’s Campus
London Bridge, London SE1 1UL, UK

Retinoic acid (RA) is the biologically active metabolite of vitamin A. It is a low molecular weight, lipophilic molecule that acts on the nucleus of cells to induce gene transcription. I will review the evidence that RA is a crucial molecule involved in the regeneration of tissues and organs. It is involved not only in the regeneration of organs from those animals which are classically known to regenerate, the Urodele amphibians, but also extends to mammals. I will describe two aspects of our own work on regeneration in mammals. Firstly, that of the stimulation of neurite regeneration from adult central nervous system neurons which it is hoped will lead to spinal cord repair and secondly that of the regeneration of alveoli in damaged adult lungs which it is hoped will lead to a treatment for lung diseases such as emphysema. In the first example, RA induces the regeneration of embryonic rat or mouse neurons through the action of one particular nuclear retinoic acid receptor, RARβ2 which is up-regulated upon RA treatment. In adult neurons this up-regulation does not occur and so the RA signal cannot switch on genes in the nucleus. When RARβ2 is transduced into adult spinal cord in vitro using a lentiviral vector system then neurite outgrowth is stimulated. We are currently testing whether this also occurs in vivo. In the second example, when lung alveoli are prevented from developing by dexamethasone administration to mouse pups the adults have the hallmarks of emphysema with a massive loss of gas exchanging surface area. By treating such adults with a series of daily doses of RA then the gas exchanging surface area can be completely regenerated within 4 weeks and the RA-treated lungs resemble those of normal animals. In both of these cases I suggest that the reason why RA induces regeneration is because it was required for the development of the organ in the first place and RA administration to adults is recapitulating those gene pathways which were used developmentally. This therefore may serve as a strategy for identifying potential tissues or organs which might have the ability to regenerate after RA adminstration.