Cytokine-Induced Activation of Signal Transducer and Activator of Transcription in Photoreceptor Precursors Regulates Rod Differentiation in the Developing Mouse Retina

Rhee, Kun Do; Goureau, Olivier; Chen, Shiming; Yang, Xian-Jie

doi:10.1523/jneurosci.1785-04.2004

Cited by 68 publications

(79 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Western blots of cell lysates, medium, or retinal extracts were processed as described previously (21,28). The amounts of viral produced hCNTF in vitro and in vivo were determined with a human CNTF Quantikine ELISA kit (R&D Systems) as described in SI Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

“…Binding of CNTF to its receptor complex activates the Jak-STAT (16), the ERK (17), and the PI3K (18) pathways. In developing and mature rodent retinas, the CNTF family of cytokines stimulates Jak-STAT and ERK signaling (19)(20)(21)(22)(23). Previous studies have revealed that the dosage and duration of CNTF treatment critically affect the function of rescued neurons.…”

mentioning

confidence: 99%

See 1 more Smart Citation

CNTF-mediated protection of photoreceptors requires initial activation of the cytokine receptor gp130 in Müller glial cells

Rhee¹,

Nusinowitz²,

Chao³

et al. 2013

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

View full text Add to dashboard Cite

Ciliary neurotrophic factor (CNTF) acts as a potent neuroprotective agent in multiple retinal degeneration animal models. Recently, CNTF has been evaluated in clinical trials for the inherited degenerative disease retinitis pigmentosa (RP) and for dry agerelated macular degeneration (AMD). Despite its potential as a broad-spectrum therapeutic treatment for blinding diseases, the target cells of exogenous CNTF and its mechanism of action remain poorly understood. We have shown previously that constitutive expression of CNTF prevents photoreceptor death but alters the retinal transcriptome and suppresses visual function. Here, we use a lentivirus to deliver the same secreted human CNTF used in clinical trials to a mouse model of RP. We found that low levels of CNTF halt photoreceptor death, improve photoreceptor morphology, and correct opsin mislocalization. However, we did not detect corresponding improvement of retinal function as measured by the electroretinogram. Disruption of the cytokine receptor gp130 gene in Müller glia reduces CNTF-dependent photoreceptor survival and prevents phosphorylation of STAT3 and ERK in Müller glia and the rest of the retina. Targeted deletion of gp130 in rods also demolishes neuroprotection by CNTF and prevents further activation of Müller glia. Moreover, CNTF elevates the expression of LIF and endothelin 2, thus positively promoting Müller and photoreceptor interactions. We propose that exogenous CNTF initially targets Müller glia, and subsequently induces cytokines acting through gp130 in photoreceptors to promote neuronal survival. These results elucidate a cellular mechanism for exogenous CNTF-triggered neuroprotection and provide insight into the complex cellular responses induced by CNTF in diseased retinas.C iliary neurotrophic factor (CNTF) belongs to a small subfamily of cytokines and has long been recognized as a potent neuroprotective molecule in the vertebrate retina (1). Enhancement of photoreceptor survival by CNTF has been demonstrated in multiple animal models of retinal degeneration, ranging from zebrafish to canine (2). Interestingly, CNTF is effective in rescuing retinal degeneration due to various causes, including mutations in genes expressed by photoreceptors or the retinal pigment epithelium (RPE), as well as those induced by strong light, neurotoxins, or antibodies. In addition, CNTF prolongs the survival of retinal ganglion cells (3-5) and promotes axonal growth in optic nerve crush or transection models (6-8). Furthermore, CNTF may affect the physiology and survival of RPE cells (9, 10), which are critical in normal vision and retinal degenerative diseases. Based on its significant and broad neuroprotective effects in damaged retinas, a secreted form of human CNTF delivered from an encapsulated cell device has been tested in clinical trials and approved by the Food and Drug Administration (FDA) to treat retinitis pigmentosa (RP) and geographic atrophy (GA), a subset of age-related macular degeneration (AMD) (11-14). However, despite its clinical signifi...

show abstract

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

CNTF-mediated protection of photoreceptors requires initial activation of the cytokine receptor gp130 in Müller glial cells

Rhee¹,

Nusinowitz²,

Chao³

et al. 2013

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

View full text Add to dashboard Cite

show abstract

“…Briefl y, cells were treated at day 3 in culture with 10 M H 2 O 2 for 30 min at 36°C; the medium was then removed, replaced with fresh decreases the intracellular levels of proapoptotic lipid signals such as ceramide ( 16 ). Activation of the ERK/MAPK pathway is also involved in the effects of peptidic trophic factors for photoreceptors, like FGF2 and ciliary neurotrophic factor ( 17,18 ). However, which upstream molecular mechanisms led to its activation by a fatty acid was an intriguing question.…”

Section: H 2 O 2 Treatmentmentioning

confidence: 99%

Retinoid X receptor activation is essential for docosahexaenoic acid protection of retina photoreceptors

German

Monaco

Agnolazza

et al. 2013

Journal of Lipid Research

View full text Add to dashboard Cite

“…Rod and cone photoreceptors have a unique and specialized function and initiate the phototransduction process by converting photons into electrical signal (14). Differentiation and homeostasis of photoreceptors are tightly controlled by a set of key transcriptional regulatory proteins, which include nuclear receptors (such as ROR␤ (15), thyroid hormone receptor ␤2 (TR␤2) (16), and NR2E3 (17)(18)(19)(20)(21)), homeodomain proteins (such as orthodenticle homeobox 2 (OTX2) (22) and CRX (cone-rod homeobox) (23,24), signal transducers (including STAT3 (25), PIAS3 (26), glycogen synthase kinase 3 (GSK3) (27)), and NRL, a basic motif-leucine zipper (bZIP) protein of Maf subfamily (28).…”

mentioning

confidence: 99%

Sumoylation of bZIP Transcription Factor NRL Modulates Target Gene Expression during Photoreceptor Differentiation

Roger

Nellissery

Kim³

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

Development of rod photoreceptors in the mammalian retina is critically dependent on the basic motif-leucine zipper transcription factor NRL (neural retina leucine zipper). In the absence of NRL, photoreceptor precursors in mouse retina produce only cones that primarily express S-opsin. Conversely, ectopic expression of NRL in post-mitotic precursors leads to a rod-only retina. Spatiotemporal control of gene expression is critical for development and homeostasis (1). Cell type-specific expression patterns are established and maintained by transient or stable interactions between cis-regulatory elements in the target genes and trans-regulatory factors that together constitute gene regulatory networks (2). Signaling molecules, another key component of gene regulatory networks, can modify the activity of transcription factors by post-translational modifications (PTMs) 3 such as phosphorylation, acetylation, ubiquitination, and sumoylation (3-6). Rapid and reversible modulation of the activity of transcription factors by PTMs is essential for adaptation to continuously changing cellular microenvironment(s) and is accomplished by altering protein stability, subcellular localization, and protein-DNA and/or protein-protein interaction (3, 6 -8). Consequently, PTMs provide a higher level of control and complexity to gene regulation in a particular biological context. The vertebrate retina exhibits a highly organized laminar structure that captures, integrates, and transmits visual signals to other parts of the central nervous system for further processing. Six neuronal cell types and Muller glia in the retina originate from pools of multipotent progenitor cells in a conserved sequential order (9, 10). The determination of specific cell fate and subsequent differentiation is dictated primarily by intrinsic control mechanisms; however, extrinsic signals modulate key steps in the developmental pathway (9 -13). Rod and cone photoreceptors have a unique and specialized function and initiate the phototransduction process by converting photons into electrical signal (14). Differentiation and homeostasis of photoreceptors are tightly controlled by a set of key transcriptional regulatory proteins, which include nuclear receptors (such as ROR␤ (15), thyroid hormone receptor ␤2 (TR␤2) (16), and NR2E3 (17-21)), homeodomain proteins (such as orthodenticle homeobox 2 (OTX2) (22) and CRX (cone-rod homeobox) (23, 24), signal transducers (including STAT3 (25), PIAS3 (26), glycogen synthase kinase 3 (GSK3) (27)), and NRL, a basic motif-leucine zipper (bZIP) protein of Maf subfamily (28).The bZIP transcription factor NRL is a key regulator of rod versus cone photoreceptor cell fate in mammalian retina (28,29). Targeted deletion of Nrl in mice leads to a retina with only cones that primarily express S-opsin (28), whereas ectopic expression of NRL in photoreceptor precursors leads to a rodonly retina (29). NRL expression is detected soon after the final mitosis and drives a photoreceptor precursor toward rod cell fate (30). NRL interacts wi...

show abstract

Cytokine-Induced Activation of Signal Transducer and Activator of Transcription in Photoreceptor Precursors Regulates Rod Differentiation in the Developing Mouse Retina

Cited by 68 publications

References 52 publications

CNTF-mediated protection of photoreceptors requires initial activation of the cytokine receptor gp130 in Müller glial cells

CNTF-mediated protection of photoreceptors requires initial activation of the cytokine receptor gp130 in Müller glial cells

Retinoid X receptor activation is essential for docosahexaenoic acid protection of retina photoreceptors

Sumoylation of bZIP Transcription Factor NRL Modulates Target Gene Expression during Photoreceptor Differentiation

Contact Info

Product

Resources

About