Origins and evolutionary diversification of the nuclear receptor superfamily

Nuclear receptors (NRs), which include those for steroid and thyroid hormones as well as retinoids, are encoded by a large gene superfamily that has evolved to regulate nearly every facet of metazoan life, from development to basic metabolism. This article reviews the conservation in structure and function of distinct receptors across different species and attempts to draw conclusions as to the evolution of this gene superfamily. Although sequences related to NRs can be found in plants and yeast, gene sequence analyses suggest that the NR ancestor(s) first appeared in the early metazoans and subsequently diversified into the six receptor sub-families, which were already recognisable at the time of the Arthropoda-Chordata split over 700 million years ago. At the time when a primitive NR emerged, the basic components of the transcription regulatory machinery, which are conserved from yeast to vertebrates, were already in place and the ancestral NR must have evolved with the ability to communicate with them. The first such NRs likely acted as monomers and in a ligand-independent fashion. As members of the NR superfamily acquired the ability to hetero- and homodimerise, and to bind and be regulated by ligands, the functional complexity of the NR superfamily increased. This exponentially increasing complexity subsequently provided a potential driving force for evolution of higher organisms by supplying a sophisticated regulatory gene network that could control complex physiological processes during development and in adult organisms.