Eye development: a view from the retina pigmented epithelium Juan Ramo ´ n Martı ´nez-Morales, Isabel Rodrigo, and Paola Bovolenta* Summary The retina pigment epithelium (RPE) is a highly specia- lised epithelium that serves as a multifunctional and indispensable component of the vertebrate eye. Although a great deal of attention has been paid to its transdiffer- entiation capabilities and its ancillary functions in neural retina development, little is known about the molecular mechanisms that specify the RPE itself. Recent advances in our understanding of the genetic network that controls the progressive specification of the eye anlage in vertebrates have provided some of the initial cues to the mechanisms responsible for RPE patterning. Here, we have outlined many recent findings that suggest that a limited number of transcription factors, including Otx2, Mitf and Pax6 and a few signalling cascades, are the elements required for the onset of RPE specification in vertebrates. Furthermore, using this information and the data available on the specification of the pigmented cells of primitive chordates, we have ventured some hypoth- eses on the origin of RPE cells during evolution. BioEssays 26:766–777, 2004. ß 2004 Wiley Periodicals, Inc. Introduction The retina pigment epithelium (RPE) is a highly polarised and specialised monolayered epithelium. As with other melanin- producing cells, cells of the RPE are characterised by the presence of the melanosome, a lysosome-related organelle devoted to the biosynthesis and storage of the melanin pigments. (1) Placed at the interface between the photoreceptors of the neural retina and the vascular meshwork of the choroid layer, the RPE is a multifunctional and indispensable component of the vertebrate eye. It participates in the outer blood–retinal barrier, maintains adhesion and water and ions flow between the neural retina and the choroid, absorbs straight light preventing the degradation of the visual image, protects against free radicals, controls retinoid metabolism and phagocytes the outer segment of the photoreceptors, ensuring their renewal. (2,3) In spite of these features that are characteristic of a homeostatic tissue, the RPE shares its origin with the neural retina as an anterior neural plate derivative. Perhaps because of this common root, the embryonic RPE is capable of transdifferentiating into a neural retina in many vertebrate species, although only urodeles retain this capability in adult stages. (4) In the past, much of the developmental biologists’ interest in RPE has been devoted to understanding these transdifferentiation capabilities or its ancillary functions on retina development, i.e. how it influences retina neurogen- esis, (5,6) its layer organisation (7) or the behaviour of retina ganglion cell axons. (8) On the contrary, little attention has been given to the molecular mechanisms that specify the RPE itself. Recent advances in studies on the genetic network that controls the progressive specification of the eye anlage in vertebrates, have provided some of the initial cues that will allow dissection of RPE development. In this review, we have summarised this information and ventured some hypotheses on the origin of RPE cells during evolution. The RPE is an anterior neural plate derivative Although it is still often stated in the literature that the eyes form as bilateral evaginations of the diencephalon, (9) one of the most accepted models of CNS regionalisation considers the eyes as structures of the secondary prosencephalon, strictly related to the telencephalic derivatives. (10) In support of this association, studies on anterior neural plate specification have highlighted a close relationship between telencephalic and eye precursor cells. (11) Furthermore, fate-map studies in different species have located the eye field to the anteriormost neural plate surrounded rostrally and laterally by telencephalic pre- cursors and caudally and medially by cells that will form the hypothalamus, (12 and references therein) which may be considered as part of the prosencephalic basal plate. (10) Unfortunately, none of these studies has specifically addressed the localisation of the RPE precursors within the eye field, although transplant experiments in chick suggest that they might be located at the 766 BioEssays 26.7 BioEssays 26:766–777, ß 2004 Wiley Periodicals, Inc. Instituto Cajal, CSIC, Madrid, Spain. Funding agencies: The Spanish MCyT, the European Community, the HFSPO and the Comunidad Auto ´ noma de Madrid. *Correspondence to: Paola Bovolenta, Instituto Cajal, CSIC, Dr Arce 37, Madrid 28002, Spain. E-mail: bovolenta@cajal.csic.es DOI 10.1002/bies.20064 Published online in Wiley InterScience (www.interscience.wiley.com). Review articles