The nuclear receptor NR2E3 plays a role in human retinal photoreceptor differentiation and degeneration

Abstract

Normal human retinal development involves orderly generation of rods and cones by complex mechanisms. Cell-fate specification involves progenitor cell lineage and external signals such as soluble factors and cell-cell interactions. In most inherited human retinal degenerations, including retinitis pigmentosa, a mutant gene causes loss of visual function, death of mature rods, and eventually death of all cone subtypes. Only one inherited retinal disorder, the enhanced S cone syndrome (ESCS), shows increased visual function, involving the minority S (blue) cones, and decreased rod and L͞M (red͞green) cone function. This autosomal recessive disease is caused by mutations in NR2E3, a photoreceptor nuclear receptor transcription factor, and may result from abnormal cell-fate determination, leading to excess S cones at the expense of other photoreceptor subtypes. In 16 ESCS patients with the most common NR2E3 mutation, R311Q, we documented an abnormal ratio of S to L͞M cone function and progressive retinal degeneration. We studied the postmortem retina of an ESCS patient homozygous for NR2E3 R311Q. No rods were identified, but cones were increased approximately 2-fold, and 92% were S cones. Only 15% of the cones expressed L͞M cone opsin, and some coexpressed S cone opsin. The retina was disorganized, with densely packed cones intermixed with inner retinal neurons. The retina was also degenerate, retaining photoreceptors in only the central and far peripheral regions. These observations suggest a key role for NR2E3 in regulation of human photoreceptor development. Degeneration of the NR2E3 retina may result from defective development, known S cone fragility, or abnormal maintenance of mature photoreceptors. T he molecular events during development of invertebrate and vertebrate retinas are incompletely understood. The specification of rods and cones involves interactions of both intrinsic and extrinsic factors, including cell lineage, soluble factors, and local cell-cell interactions (1-3). These complex signaling pathways involve nuclear receptors, a superfamily of transcription factors that share structural features, including DNA and ligandbinding domains (4, 5). A human photoreceptor-specific nuclear receptor (PNR), NR2E3, is a member of the nuclear receptor subfamily II (6). Coexpression of NR2E3, CRX (cone-rod homeobox; ref. 7), and NRL (nuclear retina leucine zipper; ref. 8) in human Y79 retinoblastoma cells suggests that NR2E3 is a component of a photoreceptor transcription cascade in human retinal development (6).Mutations in NR2E3 (9, 10) cause a unique human retinal disease, the enhanced S cone syndrome (ESCS), initially described using psychophysical and electrophysiological methods (11). ESCS patients lack rod photoreceptor function, like other inherited retinal degenerations such as retinitis pigmentosa (12), but are unique because their S (blue) cones, normally a minority population (13), are more responsive to light than the usually more populous L͞M (red͞green) cones (11, 14-16). The retinal pathology ...

NR2E3mutations in enhanced S-cone sensitivity syndrome (ESCS), Goldmann-Favre syndrome (GFS), clumped pigmentary retinal degeneration (CPRD), and retinitis pigmentosa (RP)

“…Further analyses of the patients ERG suggested that an increased number of S-cones caused the observed gain-of-function of S-cones [Hood et al, 1995]. Histological analysis of a postmortem retina from a 77-year-old ESCS patient later confirmed an absence of rods and an increase by approximately two-fold of the number of cones, 92% of which were S-cones [Milam et al, 2002]. Additional clinical findings with an important variability and onset between patients, even inside a same family, including: cystoid maculopathy; retinal degeneration in the region of the vascular arcades, ranging from yellow flecks to clumped or nummular pigment deposition; relative ring scotomas; macular retinoschisis; disorganized retinal lamination; rosette formation in the outer nuclear layer; subfoveal neovascularization; and reduced visual acuity; posterior subcapsular cataracts [Audo et al, 2008;Cideciyan et al, 2003;Greenstein et al, 1996;Jacobson et al, 1990Jacobson et al, , 2004Jurklies et al, 2001;Marmor et al, 1990;Nakamura et al, 2004;Pachydaki et al, 2009;Vaclavik et al, 2008;Yamamoto et al, 1999].…”

Regulation of photoreceptor gene expression by Crx-associated transcription factor network

“…Histopathological studies showed excess S-cones in the retina, some of which express both S-and M-cone opsins (Milam et al, 2002), which is unusual in humans (Lukats et al, 2005;Peichl, 2005).…”

In Pursuit of Synthetic Modulators for the Orphan Retina-Specific Nuclear Receptor NR2E3

“…7 As NR2E3 is expressed in both developing and adult retina, it has been suggested that in addition to its role in retinal development, this NR may be involved in photoreceptor maintenance in the adult retina. 19 The phenotype of the late-onset, slowly progressing retinal degeneration in rd7 mice, which harbor a spontaneous deletion within the Nr2e3 gene, 8 seems to be consistent with the dual function of this NR in retinal development and photoreceptor maintenance. Expression profiling conducted in the retinas of Nr2e3 -/ -and wild-type mice indicates a switch in repertoire of regulated genes at the point of transition from retinal differentiation to the fully developed adult retina, which is consistent with the dual role of Nr2e3 in photoreceptor maintenance and development.…”

“…Mutations in NR2E3 have been associated with several forms of retinal degeneration in human patients, including enhanced S-cone syndrome, [12][13][14] autosomal dominant 15,16 and recessive 17 forms of retinitis pigmentosa, Goldmann-Favre syndrome, 13 and clumped pigmentary retinal degeneration. 13 Several studies indicate that NR2E3 acts as a critical regulator of photoreceptor development 8,12,[18][19][20] where it may function as a repressor of cone-specific genes. 7 As NR2E3 is expressed in both developing and adult retina, it has been suggested that in addition to its role in retinal development, this NR may be involved in photoreceptor maintenance in the adult retina.…”