Prof. Dr. P. Escher
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.
To understand the molecular mechanisms underlying the high variability in clinical phenotypes observed in recessive and dominant NR2E3-linked retinal degenerations, we resort to structural and functional analyses in vitro and in cellular models, and generated several genetically modified mouse models. We identified so far absence of NR2E3 protein, absence of binding of NR2E3 to DNA sequences regulating photoreceptor-specific gene expression, impaired dimerization of the NR2E3 protein and a trans-repressing effect of NR2E3 towards CRX as potential disease mechanisms in NR2E3-linked retinal degenerations.
Fundus photography of 2-month-old wild-type (A: Nr2e3+/+) and knock-in mice harboring a patient-specific NR2E3 mutation (B: Nr2e3ki/ki). The white spots visible by fundus photography colocalize with the rosettes and whorls located in the outer retina of Nr2e3ki/ki mice, as imaged by optical coherence tomography (C).
Selected recent publications
1. Olivares AM, Han Y, Soto D, Flattery K, Marini J, Molemma N, Haider A, Escher P, DeAngelis MM and Haider NB. The nuclear hormone receptor gene Nr2c1 (Tr2) is a critical regulator of early retina cell patterning, Dev. Biol., 429:343-355, 2017.
2. Boulling A and Escher P. Coupling ex vivo electroporation of mouse retinas and luciferase reporter assays to assess rod-specific promoter activity, Exp. Eye Res., 148:79-82, 2016.
3. Escher P, Vaclavik V, Munier FL and Tran HV. Presence of a triple concentric autofluorescence ring in NR2E3-p.G56R-linked autosomal dominant retinitis pigmentosa (ADRP), Invest. Ophthalmol. Vis. Sci., 57:2001-2002, 2016.
4. von Alpen D, Tran HV, Guex N, Venturini G, Munier FL, Schorderet DF, Haider NB and Escher P. Differential dimerization of variants linked to enhanced S-cone sensitivity syndrome (ESCS) located in the NR2E3 ligand-binding domain, Hum. Mutat., 36:599-610, 2015.
Teaching: Basics in Neuroscience (KSL 436617)