Fibroblast growth factor–hedgehog interdependence during retina regeneration

Spence, Jason R.; Aycinena, Juan Carlos; Rio‐Tsonis, Katia Del

doi:10.1002/dvdy.21115

“…Replication-competent RCAS (A) retroviruses engineered to express a constitutively active form of BMPRIA (24) (also described in SI Materials and Methods), GFP, or noggin were produced and injected as described (14). Beads containing FGF2, SB20350 (p38 inhibitor; BioChem), or PD173074 (FGFR inhibitor; Pfizer) were prepared as described (16). See SI Materials and Methods for how eyes were fixed for each procedure and processed for histology, immunohistochemistry, and TUNEL.…”

Section: Methodsmentioning

confidence: 99%

“…In vitro explants, Western blot analysis, and real-time RT-PCR was performed as in ref. 16 with the following treatments: 10 g/ml FGF2 (R&D Systems), 1-2 g/ml BMP4 (R&D Systems), 60 ng/ml noggin (R&D Systems), and/or 2.5 M PD173074 (Pfizer). Densitometry measurements were determined by using ImageQuant 5.2 software.…”

Section: Methodsmentioning

confidence: 99%

“…The embryonic chick has been shown to regenerate a complete retina in Ϸ7 days as long as a retinectomy is performed on or around embryonic day 4 (E4) and a source of FGF is added (14,16,17). In the presence of ectopic FGF2, regeneration takes place by transdifferentiation of the retinal pigmented epithelium (RPE) and the activation of retinal stem/progenitor cells (RS/ RPCs) present in the anterior region of the eye known as the ciliary margin (CM), which ultimately houses the ciliary body and ciliary marginal zone (14,16).…”

mentioning

confidence: 99%

“…In the presence of ectopic FGF2, regeneration takes place by transdifferentiation of the retinal pigmented epithelium (RPE) and the activation of retinal stem/progenitor cells (RS/ RPCs) present in the anterior region of the eye known as the ciliary margin (CM), which ultimately houses the ciliary body and ciliary marginal zone (14,16).…”

mentioning

confidence: 99%

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BMP signaling mediates stem/progenitor cell-induced retina regeneration

Haynes¹,

Gutierrez²,

Aycinena³

et al. 2007

Proceedings of the National Academy of Sciences

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We identified a mechanism whereby retina regeneration in the embryonic chick can be induced by the contribution of stem/ progenitor cells. We show that bone morphogenetic protein (BMP) signaling is sufficient and necessary to induce retina regeneration and that its action can be divided into two phases. By 3 days after postretinectomy (d PR), the BMP pathway directs proliferation and regeneration through the activation of Smad (canonical BMP pathway) and the up-regulation of FGF signaling by the MAPK pathway. By 7d PR, it induces apoptosis by activating p38 (a noncanonical BMP pathway) and down-regulating FGF signaling (by both MAPK and AKT pathways). Apoptosis at this later stage can be prevented, and BMP-induced regeneration can be further induced by inhibition of p38. These results unravel a mechanism for stem/ progenitor cell-mediated retina regeneration, where BMP activation establishes a cross-talk with the FGF pathway and selectively activates the canonical and noncanonical BMP pathways. Retina stem/progenitor cells exist in other species, including humans. Thus, our findings provide insights on how retinal stem cells can be activated for possible regenerative therapies.p38 ͉ FGF B one morphogenetic proteins (BMPs) are secreted signaling proteins that elicit their effect by binding to a heterodimer receptor complex composed of a BMP type I receptor (BMPRIA or BMPRIB) and a BMP type II receptor (BMPRII) (1). The BMP pathway can activate the canonical downstream effector, Smad, or a noncanonical downstream effector, transforming growth factor-␤-activated kinase (TAK1) (1). Several endogenous inhibitors, including noggin, chordin, follistatin, and gremlin, can regulate the ability of BMP to activate these pathways (2).In the developing retina, BMP2, BMP4, and BMP7, as well as the BMP receptors, are expressed in the chick (3) and mouse (4-6) and have been found to play a role in establishing the dorsal/ventral patterning of the retina. They also regulate the differentiation and survival of retinal neurons (7-11). Because of the BMP pathway's importance during retina development and in stem cell biology, we wanted to examine its role in inducing and regulating retina regeneration.A population of retinal stem cells is maintained after retinal development in the anterior margin of the eye in many vertebrates, including humans (12, 13). In most vertebrates, these retinal stem cells remain quiescent and do not respond to injury. However, cells in the anterior margin of the embryonic chick eye respond to injury during a limited time of retina development, providing an opportunity to study the induction process of these stem/progenitor cells (13-15).The embryonic chick has been shown to regenerate a complete retina in Ϸ7 days as long as a retinectomy is performed on or around embryonic day 4 (E4) and a source of FGF is added (14,16,17). In the presence of ectopic FGF2, regeneration takes place by transdifferentiation of the retinal pigmented epithelium (RPE) and the activation of retinal stem/progenitor cells (RS/ R...

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“…In most vertebrates, these retinal stem cells remain quiescent and do not respond to injury. However, cells in the anterior margin of the embryonic chick eye respond to injury during a limited time of retina development, providing an opportunity to study the induction process of these stem/progenitor cells (13-15).The embryonic chick has been shown to regenerate a complete retina in Ϸ7 days as long as a retinectomy is performed on or around embryonic day 4 (E4) and a source of FGF is added (14,16,17). In the presence of ectopic FGF2, regeneration takes place by transdifferentiation of the retinal pigmented epithelium (RPE) and the activation of retinal stem/progenitor cells (RS/ RPCs) present in the anterior region of the eye known as the ciliary margin (CM), which ultimately houses the ciliary body and ciliary marginal zone (14, 16).…”

mentioning

confidence: 99%

BMP signaling mediates stem/progenitor cell-induced retina regeneration

Haynes

¹

,

Gutierrez

²

,

Aycinena

³

et al. 2007

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

Self Cite

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We identified a mechanism whereby retina regeneration in the embryonic chick can be induced by the contribution of stem/ progenitor cells. We show that bone morphogenetic protein (BMP) signaling is sufficient and necessary to induce retina regeneration and that its action can be divided into two phases. By 3 days after postretinectomy (d PR), the BMP pathway directs proliferation and regeneration through the activation of Smad (canonical BMP pathway) and the up-regulation of FGF signaling by the MAPK pathway. By 7d PR, it induces apoptosis by activating p38 (a noncanonical BMP pathway) and down-regulating FGF signaling (by both MAPK and AKT pathways). Apoptosis at this later stage can be prevented, and BMP-induced regeneration can be further induced by inhibition of p38. These results unravel a mechanism for stem/ progenitor cell-mediated retina regeneration, where BMP activation establishes a cross-talk with the FGF pathway and selectively activates the canonical and noncanonical BMP pathways. Retina stem/progenitor cells exist in other species, including humans. Thus, our findings provide insights on how retinal stem cells can be activated for possible regenerative therapies.p38 ͉ FGF B one morphogenetic proteins (BMPs) are secreted signaling proteins that elicit their effect by binding to a heterodimer receptor complex composed of a BMP type I receptor (BMPRIA or BMPRIB) and a BMP type II receptor (BMPRII) (1). The BMP pathway can activate the canonical downstream effector, Smad, or a noncanonical downstream effector, transforming growth factor-␤-activated kinase (TAK1) (1). Several endogenous inhibitors, including noggin, chordin, follistatin, and gremlin, can regulate the ability of BMP to activate these pathways (2).In the developing retina, BMP2, BMP4, and BMP7, as well as the BMP receptors, are expressed in the chick (3) and mouse (4-6) and have been found to play a role in establishing the dorsal/ventral patterning of the retina. They also regulate the differentiation and survival of retinal neurons (7-11). Because of the BMP pathway's importance during retina development and in stem cell biology, we wanted to examine its role in inducing and regulating retina regeneration.A population of retinal stem cells is maintained after retinal development in the anterior margin of the eye in many vertebrates, including humans (12, 13). In most vertebrates, these retinal stem cells remain quiescent and do not respond to injury. However, cells in the anterior margin of the embryonic chick eye respond to injury during a limited time of retina development, providing an opportunity to study the induction process of these stem/progenitor cells (13-15).The embryonic chick has been shown to regenerate a complete retina in Ϸ7 days as long as a retinectomy is performed on or around embryonic day 4 (E4) and a source of FGF is added (14,16,17). In the presence of ectopic FGF2, regeneration takes place by transdifferentiation of the retinal pigmented epithelium (RPE) and the activation of retinal stem/progenitor cells (RS/ R...

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An insight on established retinal injury mechanisms and prevalent retinal stem cell activation pathways in vertebrate models

Sherpa

¹

,

Hui

²

2021

Anim Models and Exp Med

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The brain processes visual information when light energy transduces into neural activity in the retina. The close-knit components of the central nervous system (CNS), the brain, and its extension retina are thus the critical players in visual perception, thereby aiding in daily activities. While the brain remains well protected inside the skull, the eyes are quite susceptible to physical injuries and chemical accidents. 1 Furthermore, one's genetic makeup and increasing age also invite multiple numbers of eye diseases such as retinitis pigmentosa (RP), age-related macular degeneration (AMD), glaucoma, etc All this has contributed to the recent "World Reports on vision (2019)," which shows that a whopping 2.2 billion people globally fell victim to visual impairment in the past year. 2 The discovery of the existence of adult retinal stem/progenitor cells among different vertebrate species 3 and its high reparative activity in the case of lower vertebrates has presented us with a possibility to "self-heal" the retina one day. 4 Consequently, high regeneration competent animals, which include the amphibian newts and Xenopus, teleost zebrafish (Danio rerio), and chick are thus being explored 5 to investigate different genetic and epigenetic features, signaling pathways, and factors 6,7 that regulate stem cell activation, thus gradually filling in the gaps of our knowledge of mammals, which appear to be the least competent among the group. 8 With the hope of updating and giving researchers an idea about how these animal models have significantly shaped our understanding of the retinal regeneration process, in this review,

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Fibroblast growth factor–hedgehog interdependence during retina regeneration

Cited by 45 publications

References 69 publications

BMP signaling mediates stem/progenitor cell-induced retina regeneration

BMP signaling mediates stem/progenitor cell-induced retina regeneration

BMP signaling mediates stem/progenitor cell-induced retina regeneration

An insight on established retinal injury mechanisms and prevalent retinal stem cell activation pathways in vertebrate models

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