A PDE6A Promoter Fragment Directs Transcription Predominantly in the Photoreceptor

Taylor, Russell E.; Shows, Kathryn H.; Zhao, Ying; Pittler, Steven J.

doi:10.1006/bbrc.2001.4605

Cited by 14 publications

(7 citation statements)

References 28 publications

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“…Despite the presence of rudimentary discs contained within shortened outer segments, the Nrl Ϫ/Ϫ mouse displays very low to no expression of several rod photoreceptor-specific markers including Pde6b (19). It seems most likely that the Pde6a signal detected in Nrl-null mice is from inner retinal cells, consistent with our previous report showing in situ hybridization labeling in the inner nuclear layer of adult mouse retina (12).…”

Section: Discussionsupporting

confidence: 89%

“…A DNase I footprinting region was identified within the first 100 upstream nucleotides that was confirmed by the demonstration of a retina-specific mobility shift. The promoter region was delimited to within a 177-bp upstream region that is active both in vitro (11) and in vivo in transgenic mice (12). Contained within this region are several potential cis-elements that may bind retina-specific transcription factors including CRX sites (Crx binding element (CBE)) and a non-consensus NRL-like site (Nrl response element (NRE)).…”

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confidence: 99%

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

Pittler

Zhang

Chen

et al. 2004

Journal of Biological Chemistry

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To understand the factors controlling expression of the cGMP phosphodiesterase type 6 (PDE6) genes, we have characterized the promoter of the human PDE6A gene that encodes the catalytic ␣-subunit. In vivo DNase I hypersensitivity assays revealed two sites immediately upstream of the PDE6A core promoter region. Transient transfection assay in Y79 cells of constructs containing varying lengths of the promoter region showed a decrease in promoter activity with increasing length. The most active segment contained a 177-bp upstream sequence including apparent Crx and Nrl transcription factor binding sites. Both Crx and Nrl transactivated the PDE6A promoter in HEK293 cells and showed a >100-fold increase when coexpressed. Coexpression of a dominant negative inhibitor of Nrl abolished Nrl transactivation but had no effect on Crx. DNase I footprinting assays identified three potential Crx binding sites within a 55-bp segment beginning 29 bp upstream of the transcription start point. Mutation of two of these sites reduced reporter gene activity by as much as 69%. Gel shifts showed that all three Crx sites required a TAAT sequence for efficient binding. Consistent with a requirement for Crx and Nrl in Pde6a promoter activity, Pde6a mRNA is reduced by 87% in the retina of Crx ؊/؊ mice and is undetectable in Nrl ؊/؊ mice at postnatal day 10. These results establish that both Nrl and Crx are required for full transcriptional activity of the PDE6A gene.

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Section: Discussionsupporting

confidence: 89%

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confidence: 99%

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

Pittler

Zhang

Chen

et al. 2004

Journal of Biological Chemistry

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“…The complex patterns of expression of the PDE genes strongly suggest that a number of developmental, hormonal, signal-induced and tissuespecific factors must be involved in regulating transcription of the PDE genes. However, most of the actual transcription factors and regulatory circuits controlling expression of the PDE genes are still unknown, as identification of the corresponding promoter regions has been reported for only very few PDE genes (PDE3B, PDE4D, PDE5A and PDE6A) [3][4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Functional characterization of the human phosphodiesterase 7A1 promoter

Torras-Llort

Azorı́n

2003

Biochemical Journal

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In this paper, the human phosphodiesterase 7A1 (hPDE7A1) promoter region was identified and functionally characterized. Transient transfection experiments indicated that a 2.9 kb fragment of the hPDE7A1 5 -flanking region, to position − 2907, has strong promoter activity in Jurkat T-cells. Deletion analysis showed that the proximal region, up to position − 988, contains major cis-regulatory elements of the hPDE7A1 promoter. This minimal promoter region contains a regulatory CpG island which is essential for promoter activity. The CpG island contains three potential cAMP-response-element-binding protein (CREB)-binding sites that, as judged by in vivo dimethyl sulphate (DMS) footprinting, are occupied in Jurkat T-cells. Moreover, overexpression of CREB results in increased promoter activity, but, on the other hand, promoter activity decreases when a dominantnegative form of CREB (KCREB) is over-expressed. In vivo DMS footprinting strongly indicates that other transcription factors, such Ets-2, nuclear factor of activated T-cells 1 (NFAT-1) and nuclear factor κB (NF-κB), might also contribute to the regulation of hPDE7A1 promoter. Finally, hPDE7A1 promoter was found to be induced by treatment with PMA, but not by treatment with dibutyryl cAMP or forskolin. These results provide insights into the factors and mechanisms that regulate expression of the hPDE7A gene.

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“…Despite PDE6 presence is only described in retina photoreceptors [33], we also studied its expression in SVZ-derived NSC cultures since some of the inhibitors for PDE5 also act on PDE6. The expression of several PDEs normally found in the brain was analyzed in SVZ cultures by reverse-transcription PCR.…”

Section: Resultsmentioning

confidence: 99%

Stimulation of Neural Stem Cell Proliferation by Inhibition of Phosphodiesterase 5

Santos

Carreira

Nobre

et al. 2014

Stem Cells International

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The involvement of nitric oxide (NO) and cyclic GMP (cGMP) in neurogenesis has been progressively unmasked over the last decade. Phosphodiesterase 5 (PDE5) specifically degrades cGMP and is highly abundant in the mammalian brain. Inhibition of cGMP hydrolysis by blocking PDE5 is a possible strategy to enhance the first step of neurogenesis, proliferation of neural stem cells (NSC). In this work, we have studied the effect on cell proliferation of 3 inhibitors with different selectivity and potency for PDE5, T0156, sildenafil, and zaprinast, using subventricular zone-(SVZ-) derived NSC cultures. We observed that a short- (6 h) or a long-term (24 h) treatment with PDE5 inhibitors increased SVZ-derived NSC proliferation. Cell proliferation induced by PDE5 inhibitors was dependent on the activation of the mitogen-activated protein kinase (MAPK) and was abolished by inhibitors of MAPK signaling, soluble guanylyl cyclase, and protein kinase G. Moreover, sildenafil neither activated ERK1/2 nor altered p27Kip1 levels, suggesting the involvement of pathways different from those activated by T0156 or zaprinast. In agreement with the present results, PDE5 inhibitors may be an interesting therapeutic approach for enhancing the proliferation stage of adult neurogenesis.

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A PDE6A Promoter Fragment Directs Transcription Predominantly in the Photoreceptor

Cited by 14 publications

References 28 publications

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

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

Functional characterization of the human phosphodiesterase 7A1 promoter

Stimulation of Neural Stem Cell Proliferation by Inhibition of Phosphodiesterase 5

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