Nuclear receptors in retinal development

The vertebrate retina is a model system for neuronal development. Vertebrate retinal histogenesis is characterized by an evolutionarily-conserved sequential birth of retinal cell classes with a substantial temporal overlap in the time windows for the generation of the different retinal neurons and glial cell from the initial pool of retinal progenitor cells. A central question in retinal development is therefore to understand what drives a retinal progenitor cell, unrestricted in cell fate, to undergo mitosis, and then the post-mitotic precursor cells to undergo terminal differentiation towards a specific cell fate.

Photoreceptors are the sensory neurons of the retina, capable to transform light into nerve impulses. There are two kinds of photoreceptors, bright light- and color-sensitive cones and dim light-sensitive rods. In the mouse retina, cone photoreceptors sensitive to blue light (‘blue cones’) are the first photoreceptors to be differentiated during embryonic development. Rod precursors are generated over an extended period of time, starting at embryonic day 13 in the central retina, peaking around birth and ongoing until postnatal day 6. We study the transcriptional network regulating development, terminal differentiation and maintenance of cone and rod photoreceptors. Several members of the ligand-activated nuclear hormone receptor family are involved in the terminal differentiation of photoreceptors.

NR2E3-linked retinal degenerations 

For instance, the photoreceptor-specific nuclear receptor NR2E3 is necessary to specify proper rod precursor development and to suppress cone-specific gene expression in rods. Specifically, in the absence of NR2E3, early-born rod precursor cells are committed to ‘blue’ cone cell fate resulting in an about 2-fold increase in ‘blue’ cones, and the rods are non-functional hybrid photoreceptors, expressing both rod- and cone-specific genes. In human, recessive mutations in NR2E3 cause enhanced S-cone sensitivity syndrome (ESCS) also called Goldmann-Favre syndrome: ‘blue’ cones hyperproliferate forming whorls and rosettes in the outer retina, whereas the rods express both rod- and cone-specific genes and are therefore non-functional. Consequently, patients show a pathognomonic increase in sensitivity to blue light and are night blind. We also identified a unique dominant NR2E3 mutation causing a more severe retinal degeneration called retinitis pigmentosa, affecting first rods, and, later in life, cone photoreceptors.