Expression profiling of the developing and mature Nrl −/− mouse retina: identification of retinal disease candidates and transcriptional regulatory targets of Nrl

Yoshida, Shigeo; Mears, Alan J.; Friedman, James S.; Carter, Todd; He, Shirley; Oh, Edwin C.; Jing, Yuezhou; Farjo, Rafal; Fleury, Gilles; Barlow, Carrolee; Hero, Alfred O.; Swaroop, Anand

doi:10.1093/hmg/ddh160

Cited by 157 publications

(184 citation statements)

References 63 publications

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“…Besides regulating the expression of Nr2e3 in the rod pathway, Nrl also binds to the Trβ2, Rxrγ, and Rorβ promoters in the cone pathway (Figure 3). This likely results in repression of Rxrγ, and Rorβ, as they are increased in Nrl −/− retinae [ Table 2 and (Yoshida et al, 2004)]. Although we did not detect significant changes in Trβ2 expression levels or in Trβ2 protein binding to target promoters in Nrl −/− or Nr2e3 −/− mice, under physiological conditions in the wild-type background Nrl could play a role in repressing Trβ2 expression either directly or indirectly.…”

Section: Auto- Para-and Feedback Regulation-mentioning

confidence: 83%

“…This was further demonstrated by mouse studies showing that ectopic expression of Nr2e3 in photoreceptor precursors of Nrl −/− mice can transform developing cones to rod-like photoreceptors . Microarray analyses of the developing and mature retina of wild-type and Nrl −/− mice have identified clusters of Nrl target genes (Yoshida et al, 2004;Yu et al, 2004;Akimoto et al, 2006). These not only include genes coding for phototransduction and structural or membrane associated proteins as expected, but also transcriptional regulators, intracellular transport proteins and components of known signaling pathways.…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

“…For example, the rod factor Nrl binds to its own promoter and auto-activates it, as only 40% of WT reporter transcript levels are seen in Nrl −/− mice carrying a transgene under the control of the Nrl promoter (Yoshida et al, 2004). Besides regulating the expression of Nr2e3 in the rod pathway, Nrl also binds to the Trβ2, Rxrγ, and Rorβ promoters in the cone pathway (Figure 3).…”

Section: Auto- Para-and Feedback Regulation-mentioning

confidence: 99%

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

2008

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Rod and cone photoreceptors in the mammalian retina are special types of neurons that are responsible for phototransduction, the first step of vision. Development and maintenance of photoreceptors require precisely regulated gene expression. This regulation is mediated by a network of photoreceptor transcription factors centered on Crx, an Otx-like homeodomain transcription factor. The cell type (subtype) specificity of this network is governed by factors that are preferentially expressed by rods or cones or both, including the rod-determining factors neural retina leucine zipper protein (Nrl) and the orphan nuclear receptor Nr2e3; and cone-determining factors, mostly nuclear receptor family members. The best-documented of these include thyroid hormone receptor β2 (Trβ2), retinoid related orphan receptor Rorβ, and retinoid X receptor Rxrγ. The appropriate function of this network also depends on general transcription factors and co-factors that are ubiquitously expressed, such as the Sp zinc finger transcription factors and STAGA coactivator complexes. These cell type-specific and general transcription regulators form complex interactomes; mutations that interfere with any of the interactions can cause photoreceptor development defects or degeneration. In this manuscript, we review recent progress on the roles of various photoreceptor transcription factors and interactions in photoreceptor subtype development. We also provide evidence of auto-, para-, and feedback regulation among these factors at the transcriptional level. These protein-protein and protein-promoter interactions provide precision and specificity in controlling photoreceptor subtype-specific gene expression, development and survival. Understanding these interactions may provide insights to more effective therapeutic interventions for photoreceptor diseases.

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Section: Auto- Para-and Feedback Regulation-mentioning

confidence: 83%

Section: Mechanisms Of Actionmentioning

confidence: 99%

Section: Auto- Para-and Feedback Regulation-mentioning

confidence: 99%

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

2008

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“…3a). Nrl is essential for the optimal expression of various rod phototransduction genes, including Rho, Gnat1 and Pdeb Yoshida et al, 2004); expression of these genes was augmented in JunAA mice (Fig. 3a).…”

Section: Expression Levels Of Nrl and Its Target Genes Are Enhanced Wmentioning

confidence: 99%

Preventing polyglutamine-induced activation of c-Jun delays neuronal dysfunction in a mouse model of SCA7 retinopathy

Mérienne¹,

Friedman²,

Akimoto³

et al. 2007

Neurobiology of Disease

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We have approached the role of cellular stress in neurodegenerative diseases caused by polyglutamine expansion (polyQ) in the context of Spinocerebellar ataxia type 7 (SCA7) that includes retinal degeneration. Using the R7E mouse, in which polyQ-ataxin-7 is specifically over-expressed in rod photoreceptors, we previously showed that rod dysfunction correlated to moderate and prolonged activation of the JNK/c-Jun stress pathway. SCA7 retinopathy was also associated with reduced expression of rod-specific genes, including the transcription factor Nrl, which is essential for rod differentiation and function. Here, we report that R7E retinopathy is improved upon breeding with the JunAA knock-in mice, in which JNK-mediated activation of c-Jun is compromised. Expression of Nrl and its downstream targets, which are involved in phototranduction, are partially restored in the JunAA-R7E mice. We further show that c-Jun can directly repress the transcription of Nrl. Our studies suggest that polyQ-induced cellular stress leads to repression of genes necessary for neuronal fate and function.

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“…NRL interacts with the homeodomain protein CRX (28), orphan nuclear receptor NR2E3 (29), and other retinal proteins (30)(31)(32) to regulate the expression of rod-specific genes (26,33). NRL is essential for rod differentiation, because rods are transformed to functional S-cones in the Nrl Ϫ/Ϫ mouse retina (26,34,35).…”

mentioning

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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138

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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Expression profiling of the developing and mature Nrl −/− mouse retina: identification of retinal disease candidates and transcriptional regulatory targets of Nrl

Cited by 157 publications

References 63 publications

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

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

Preventing polyglutamine-induced activation of c-Jun delays neuronal dysfunction in a mouse model of SCA7 retinopathy

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

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