Identification of a photoreceptor cell-specific nuclear receptor

Abstract

Nuclear receptors comprise a large and expanding family of transcription factors involved in diverse aspects of animal physiology and development, the functions of which can be modulated in a spatial and temporal manner by access to small lipophilic ligands and/or the specificity of their own localized expression. Here we report the identification of a human nuclear receptor that reveals a unique proximal box (CNGCSG) in the DNA-binding domain. The conservation of this feature in its nematode counterpart suggests the requirement for this type of P box in the genetic cascades mediated by nuclear receptors in a wide variety of animal species. The expression of this receptor, PNR (photoreceptor-specific nuclear receptor), appears strongly restricted in the retina, exclusively in photoreceptor cells. In human cell lines, PNR expression was observed in Y79 retinoblastoma along with other photoreceptor marker genes such as CRX. Among vertebrate receptors, PNR shares structural kinship with an orphan receptor TLX, and despite distinct differences in the DNA binding domain, PNR is able to recognize a subset of TLX target sequences in vitro. Analyses of the human PNR gene revealed its chromosomal position as 15q24, a site that has recently been reported as a susceptible region for retinal degeneration. These data support a role for PNR in the regulation of signalling pathways intrinsic to the photoreceptor cell function.

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

“…c) Direct target gene studies suggest that Nr2e3 is a dual transcription regulator for both rod and cone genes. In vitro protein-DNA binding assays initially showed that Nr2e3 recognizes a consensus DNA sequence with a direct repeat and binds as a homodimer (Kobayashi et al, 1999;Chen et al, 2005). This binding appears to mediate transcriptional repression rather than activation as previously observed for the rhodopsin promoter .…”

“…of rods-The nuclear orphan receptor Nr2e3 (photoreceptor-specific nuclear receptor, PNR) was originally identified by its homology to the orphan nuclear receptor tailless (Tlx, Nr2e1) initially found in Drosophila, and by its specific expression in retinal photoreceptor cells (Kobayashi et al, 1999). Similar to other members of the Tlx nuclear receptor family, Nr2e3 has a zinc-finger DNA-binding domain near the N-terminus and a ligand-binding domain in the C-terminus for a ligand yet to be identified [ (Kobayashi et al, 1999); Figure 1].…”

“…Similar to other members of the Tlx nuclear receptor family, Nr2e3 has a zinc-finger DNA-binding domain near the N-terminus and a ligand-binding domain in the C-terminus for a ligand yet to be identified [ (Kobayashi et al, 1999); Figure 1]. Nr2e3 is expressed in retinal photoreceptor cells beginning around E18 in the mouse, peaking during rod differentiation and persisting into adulthood at a decreased level (Kobayashi et al, 1999;Takezawa et al, 2007). Expression appears primarily localized to the outer nuclear layer (Kobayashi et al, 1999;Haider et al, 2000;Haider et al, 2001).…”

“…Nr2e3 is expressed in retinal photoreceptor cells beginning around E18 in the mouse, peaking during rod differentiation and persisting into adulthood at a decreased level (Kobayashi et al, 1999;Takezawa et al, 2007). Expression appears primarily localized to the outer nuclear layer (Kobayashi et al, 1999;Haider et al, 2000;Haider et al, 2001). This persistent expression, mainly in rods in mammals (Bumsted O'Brien et al, 2004;Chen et al, 2005;, suggests that Nr2e3 plays a major role in rod differentiation and maintenance.…”

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

“…Nuclear receptor, class 2, subfamily E, member 3 (NR2E3; MIM] 604485), also called photoreceptor-specific nuclear receptor (PNR), is a member of the nuclear hormone receptor superfamily of ligand-modulated transcription factors [Kobayashi et al, 1999]. The NR2E3 gene is located on chromosome 15q22.32 and spans over 7.5 kb (Fig.…”