Photoreceptor Cell Development Regulation

Photoreceptors, the specialised cells that signal visual information, evolved ∼600 million years ago, well before the divergence of vertebrates and invertebrates. Metazoan organisms have since evolved variant developmental circuitries that involve specific extrinsic and intrinsic factors to form distinct types of photoreceptor cells. Owing to studies on animal models and human ocular anomalies, the characterisation of several regulatory genes that are essential for mammalian photoreceptor development, namely CRX, NRL and NR2E3, has progressed significantly. These studies have now been further extended by the application of systems level analyses, which have begun to elucidate the underlying gene regulatory network (GRN) for photoreceptor differentiation. Insights from these studies have identified therapeutic targets and have allowed the development of protocols for the derivation of photoreceptors from mammalian embryonic stem (ES) cells and induced pluripotent stem (iPS) cells. Together with the added identification of regulatory roles for microRNAs (ribonucleic acid) and posttranslational modifications, photoreceptor development presents an unprecedented opportunity for developing regenerative medicine-based therapeutic applications for ocular diseases. Key Concepts: Photoreceptors are specialised neuronal cells that absorb and signal electromagnetic radiation-based information, that is photons, via alterations in their membrane potential. Rhabdomeric photoreceptors are predominantly, but not exclusively, found to play a visual sensory role in invertebrates and are characterised by the folding of their apical cell surface into numerous microvilli, which function to store photopigments. Ciliary photoreceptors are predominantly, but not exclusively, found to play a visual sensory role in vertebrates and are characterised by the extensive folding of their ciliary membranes for storage of photopigments. Retinal progenitor cells pass through successive states of ‘developmental competence’, which are orchestrated by a network of temporally expressed intrinsic transcription factors and signalling molecules that regulate the ability of individual cells to differentiate into specific retinal cell types. In early oculogenesis, the Notch receptor functions to repress photoreceptor differentiation in multipotent retinal progenitor cells. Loss of just one transcription factor, Nrl, leads to the complete transformation of rod precursor cells into cone photoreceptor cells in mice. Posttranscriptional events, for example, microRNA-mediated regulation, are required for achieving appropriate levels of regulatory factors that control photoreceptor differentiation in insects. Posttranslational events, for example, SUMOylation of key regulatory molecules, are essential for achieving activation of rod-expressed genes and repression of cone-expressed genes in mammalian rod photoreceptor development. High-throughput genomic technologies like microarrays, deep-sequencing and serial analysis of gene expression (SAGE), among others, will lead to a thorough analysis of photoreceptor-expressed transcripts, which in turn allows for the construction of the underlying gene regulatory networks (GRNs). Information gained from the functional characterisation of signalling molecules, transcription factors and gene regulatory networks that operate in photoreceptor cell development, are essential for the identification of potential therapeutic targets, and can also be applied to direct the differentiation of embryonic stem (ES) cells and induced pluripotent stem (iPS) cells to photoreceptor cell fates. Keywords: photoreceptor; opsin; retina; gene regulatory network (GRN); stem cells