Functional Analysis of the Rod Photoreceptor cGMP Phosphodiesterase α-Subunit Gene Promoter

Pittler, Steven J.; Zhang, Youwen; Chen, Shiming; Mears, Alan J.; Zack, Donald J.; Ren, Zhiyong; Swain, Prabodh K.; Yao, Suxia; Swaroop, Anand; White, Brandon

doi:10.1074/jbc.m401864200

Cited by 54 publications

(41 citation statements)

References 31 publications

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“…It was reported that Crx, Nrl, and Nr2e3 synergistically regulate the expression of rod-specific genes (31,(38)(39)(40)(41)(42). In the current study, we found that although the expression levels of Crx, Nrl, and Nr2e3 were similar between control and Rax iCKO (P4 ¡ P20) mouse retinas, the levels of transcripts of rod-specific genes significantly decreased in the Rax iCKO (P4 ¡ P20) mouse retina (Fig.…”

Section: Resultsmentioning

confidence: 40%

Rax Homeoprotein Regulates Photoreceptor Cell Maturation and Survival in Association with Crx in the Postnatal Mouse Retina

Irie

Sanuki

Muranishi

et al. 2015

Molecular and Cellular Biology

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A number of homeodomain transcription factors, which play significant roles in retinal development, have been identified in vertebrates (1-4). Rax is a homeodomain transcription factor that is essential for various processes in vertebrate retinal development (5). The Rax gene was first identified as a paired-type homeobox gene expressed in the optic vesicle and the presumptive diencephalon area in the early mouse embryo (6, 7). Rax is evolutionarily well conserved from Drosophila melanogaster to humans. Rax is highly expressed in retinal progenitor cells (RPCs), and its expression in the retina gradually decreases as RPCs become postmitotic and begin to differentiate. Rax-null mutant mice exhibit a reduction of brain size and an absence of the optic vesicle (5, 7). Mutations in human RAX are associated with anophthalmia and microphthalmia (8, 9). Rax overexpression promotes the proliferation of RPCs in frogs and zebra fish (7,(10)(11)(12)(13). In addition to the function in RPCs, Rax plays significant roles in the development of photoreceptor cells and Müller glial cells (14)(15)(16)(17)(18)(19).Rax paralog genes have been identified in various vertebrate species (20)(21)(22). In Xenopus laevis, two Rax genes (xRx and xRx-L/xRx2) have been identified (7, 21), and in zebra fish, three Rax genes (zRx1 to zRx3) have been isolated (7). Interestingly, the expression pattern of zebra fish Rx3 showed more similarity to that of frog and mouse Rax genes than to that of the zebra fish Rx1 and Rx2 genes (23). In chicks, two Rax genes (cRax and cRaxL/ cRax2) have been identified (20). The chick Rax2 gene is expressed in both retinal progenitor cells and early-developing photoreceptors, while chick Rax is predominantly expressed in retinal progenitor cells. It was also reported that chick Rax2 is implicated in cone photoreceptor differentiation and that the expression of a putative dominant negative allele of a chick Rax2 gene caused a significant reduction in the level of expression of cone photoreceptor genes (20). Human RAX2/QRX, which is expressed in the outer nuclear layer (ONL) and inner nuclear layer (INL) of the adult human retina, was identified to be a PCE-1-binding protein by acting synergistically with CRX and NRL to modulate the expression of photoreceptor genes. Monkey, cow, and dog genomes also contain two Rax genes. On the other hand, the Rax2 gene is absent from mouse and rat genomes (22). This raises the question of whether mouse Rax plays an essential role in photoreceptor development during postnatal stages like human Rax2 does.In the current study, we investigated a functional role for Rax in postnatal mouse retinas, which contain a single Rax gene. We report that mouse Rax modulates the expression of photoreceptor genes in the postnatal retina by interacting with Crx. Conditional ablation of Rax in postnatal photoreceptors led to a significant decrease in the level of expression of rod and cone genes and to cone photoreceptor cell death, suggesting that Rax is essential for the maturation of rods and co...

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Section: Resultsmentioning

confidence: 40%

Rax Homeoprotein Regulates Photoreceptor Cell Maturation and Survival in Association with Crx in the Postnatal Mouse Retina

Irie

Sanuki

Muranishi

et al. 2015

Molecular and Cellular Biology

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“…Another key transcription factor, Nrl, which regulates many photoreceptor-specific genes and the terminal differentiation of rod photoreceptors (98)(99)(100)(101)(102)(103), is reduced slightly (by ∼1.2 fold) in the retina of miR-183C…”

Section: Discussionmentioning

confidence: 99%

Inactivation of the microRNA-183/96/182cluster results in syndromic retinal degeneration

Lumayag

Haldin

Corbett

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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176

241

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The microRNA-183/96/182 cluster is highly expressed in the retina and other sensory organs. To uncover its in vivo functions in the retina, we generated a knockout mouse model, designated "miR-183CGT/GT ," using a gene-trap embryonic stem cell clone. We provide evidence that inactivation of the cluster results in early-onset and progressive synaptic defects of the photoreceptors, leading to abnormalities of scotopic and photopic electroretinograms with decreased b-wave amplitude as the primary defect and progressive retinal degeneration. In addition, inactivation of the miR-183/96/ 182 cluster resulted in global changes in retinal gene expression, with enrichment of genes important for synaptogenesis, synaptic transmission, photoreceptor morphogenesis, and phototransduction, suggesting that the miR-183/96/182 cluster plays important roles in postnatal functional differentiation and synaptic connectivity of photoreceptors. M icroRNAs (miRNAs) are small, endogenous, noncoding, regulatory RNAs and represent a newly recognized level of gene-expression regulation (1-4). miRNAs have unique expression profiles in the developing and adult retina and are involved in normal development and functions of the retina in all species studied so far (5-12). miRNAs are dysregulated in the retina of retinal degenerative mouse models, suggesting their potential involvement in retinal degeneration (13,14). Conditional inactivation of dicer, an RNase III endonuclease required for miRNA maturation in cytosol (15), in the mouse retina resulted in alteration of retinal differentiation and optic-cup patterning, increased cell death, and disorganization of axons of retinal ganglion cells (16)(17)(18)(19), suggesting that miRNAs are important for normal development and functions of the mammalian retina. However, in vivo functions of individual miRNAs in the retina still are largely unknown.Previously, we identified a highly conserved, intergenic, sensory organ-specific, paralogous miRNA cluster, the miR-183/96/182 cluster (hereafter, miR-183/96/182), contained within an ∼4-kb genomic segment on mouse chr6qA3.3 (8, 9). In the adult retina, miR-183/96/182 is expressed specifically in all photoreceptors and in the inner nuclear layer (8, 10). Developmentally, its expression is minimal in the embryonic retina but increases dramatically after birth and peaks in the adult retina, suggesting a role for miR-183/ 96/182 in maturation and normal functioning of the adult retina (8, 9). Additionally, expression of miR-183/96/182 has a diurnal pattern, suggesting a potential role in rhythmic functions of the retina (8, 9). Recently, miR-183/96/182 also was shown to be light responsive, independent of the circadian cycle (20). Targeted deletion of miR-182 alone in mouse did not result in a discernible phenotype, suggesting functional compensation by miR-183 and miR-96 (21). Point mutations of miR-96 were reported to result in progressive, nonsyndromic hearing loss in both human (22) and mouse (23); however, there was no apparent retinal phenotype, an ob...

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“…NRL is established as a positive transcriptional regulator of rod-specific genes (28,31,33,(45)(46)(47). To examine whether NRL can directly modulate cone-specific promoters, we screened 3 kb of 5Ј upstream promoter regions of the two cone-expressed genes, Thrb [encoding Tr␤2 that is involved in M-cone differentiation, (14)] and S-opsin, for the presence of Nrl or Maf response element (NRE/MARE) (46).…”

Section: Ectopic Expression Of Nrl Can Suppress Cone Function and Indmentioning

confidence: 99%

Transformation of cone precursors to functional rod photoreceptors by bZIP transcription factor NRL

Oh¹,

Khan²,

Novelli

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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141

153

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Networks of transcriptional regulatory proteins dictate specification of neural lineages from multipotent retinal progenitors. Rod photoreceptor differentiation requires the basic motifleucine zipper (bZIP) transcription factor NRL, because loss of Nrl in mice (Nrl ؊/؊ ) results in complete transformation of rods to functional cones. To examine the role of NRL in cell fate determination, we generated transgenic mice that express Nrl under the control of Crx promoter in postmitotic photoreceptor precursors of WT and Nrl ؊/؊ retina. We show that NRL expression, in both genetic backgrounds, leads to a functional retina with only rod photoreceptors. The absence of cones does not alter retinal lamination, although cone synaptic circuitry is now recruited by rods. Ectopic expression of NRL in developing cones can also induce rod-like characteristics and partially suppress cone-specific gene expression. We show that NRL is associated with specific promoter sequences in Thrb (encoding TR␤2 transcription factor required for M-cone differentiation) and S-opsin and may, therefore, directly participate in transcriptional suppression of cone development. Our studies establish that NRL is not only essential but is sufficient for rod differentiation and that postmitotic photoreceptor precursors are competent to make binary decisions during early retinogenesis.cell fate determination ͉ development ͉ gene regulation ͉ retina ͉ synaptic organization N euronal cell fate is determined by a hierarchical, stepwise process of binary decisions, commencing with multipotent progenitors that give rise to distinct cell lineages (1-3). The neural retina is an attractive model to investigate cell-fate determination; it contains seven major cell types that derive from common pool(s) of multipotent progenitor cells (4, 5). These retinal progenitors pass through sequential waves of competence, during which postmitotic cells can be specified to only a subset of neuronal fates (1, 6). Birth-dating studies in rodents indicate that ganglion cells, horizontal cells, cone photoreceptors, and amacrine cells are born prenatally, whereas most rod photoreceptors, bipolar cells, and Müller glia are generated postnatally (7-9). The orderly sequence of cell birth and a considerable overlap in their generation suggest a sequential program of cell intrinsic mechanisms and extrinsic signals that control cell fate decisions (10-16).Each neuronal lineage is meticulously established by highly coordinated transcription factor network(s) in response to local microenvironmental cues (17). Although extrinsic factors can promote differentiation (18,19), heterochronic mixing experiments demonstrate that progenitor cells at a particular time in development cannot be induced to generate temporally inappropriate cell types (1,20). Additionally, intrinsic priming of retinal progenitors appears to supersede the influence of environmental signals in specifying cell fate (21). Whether commitment of lineage-restricted precursors to a specific differentiation pathway is unidire...

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Functional Analysis of the Rod Photoreceptor cGMP Phosphodiesterase α-Subunit Gene Promoter

Cited by 54 publications

References 31 publications

Rax Homeoprotein Regulates Photoreceptor Cell Maturation and Survival in Association with Crx in the Postnatal Mouse Retina

Rax Homeoprotein Regulates Photoreceptor Cell Maturation and Survival in Association with Crx in the Postnatal Mouse Retina

Inactivation of the microRNA-183/96/182cluster results in syndromic retinal degeneration

Transformation of cone precursors to functional rod photoreceptors by bZIP transcription factor NRL

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