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Elena B. Pasquale - One of the best experts on this subject based on the ideXlab platform.

  • Attenuation of Eph Receptor Kinase Activation in Cancer Cells by Coexpressed
    2016
    Co-Authors: Ephrin Ligands, Giulia Falivelli, Erika Mathes Lisabeth, Elena Rubio De La Torre, Gizeh Perez-tenorio, Ombretta Salvucci, Elena B. Pasquale
    Abstract:

    The Eph receptor tyrosine kinases mediate juxtacrine signals by interacting “in trans ” with ligands anchored to the surface of neighboring cells via a GPI-anchor (Ephrin-As) or a transmembrane segment (Ephrin-Bs), which leads to receptor clustering and increased kinase activity. Additionally, soluble forms of the Ephrin-A ligands released from the cell surface by matrix metalloproteases can also activate EphA receptor signaling. Besides these trans interactions, recent studies have revealed that Eph receptors and Ephrins coexpressed in neurons can also engage in lateral “cis” associations that attenuate receptor activation by Ephrins in trans with critical functional consequences. Despite the importance of the Eph/Ephrin system in tumorigenesis, Eph receptor-Ephrin cis interactions have not been previously investigated in cancer cells. Here we show that in cancer cells, coexpressed Ephrin-A3 can inhibit the ability of EphA2 and EphA3 to bind Ephrins in trans and become activated, while Ephrin-B2 can inhibit not only EphB4 but also EphA3. The cis inhibition of EphA3 by Ephrin-B2 implies that in some cases Ephrins that cannot activate a particular Eph receptor in trans can nevertheless inhibit its signaling ability through cis association. We also found that an EphA3 mutation identified in lung cancer enhances cis interaction with Ephrin-A3. These results suggest a novel mechanism that may contribute to cancer pathogenesis by attenuating the tumor suppressing effects of Eph recepto

  • attenuation of eph receptor kinase activation in cancer cells by coexpressed Ephrin ligands
    PLOS ONE, 2013
    Co-Authors: Elena B. Pasquale, Giulia Falivelli, Erika Mathes Lisabeth, Elena Rubio De La Torre, Ombretta Salvucci, Gizeh Pereztenorio, Giovanna Tosato
    Abstract:

    The Eph receptor tyrosine kinases mediate juxtacrine signals by interacting "in trans" with ligands anchored to the surface of neighboring cells via a GPI-anchor (Ephrin-As) or a transmembrane segment (Ephrin-Bs), which leads to receptor clustering and increased kinase activity. Additionally, soluble forms of the Ephrin-A ligands released from the cell surface by matrix metalloproteases can also activate EphA receptor signaling. Besides these trans interactions, recent studies have revealed that Eph receptors and Ephrins coexpressed in neurons can also engage in lateral "cis" associations that attenuate receptor activation by Ephrins in trans with critical functional consequences. Despite the importance of the Eph/Ephrin system in tumorigenesis, Eph receptor-Ephrin cis interactions have not been previously investigated in cancer cells. Here we show that in cancer cells, coexpressed Ephrin-A3 can inhibit the ability of EphA2 and EphA3 to bind Ephrins in trans and become activated, while Ephrin-B2 can inhibit not only EphB4 but also EphA3. The cis inhibition of EphA3 by Ephrin-B2 implies that in some cases Ephrins that cannot activate a particular Eph receptor in trans can nevertheless inhibit its signaling ability through cis association. We also found that an EphA3 mutation identified in lung cancer enhances cis interaction with Ephrin-A3. These results suggest a novel mechanism that may contribute to cancer pathogenesis by attenuating the tumor suppressing effects of Eph receptor signaling pathways activated by Ephrins in trans.

  • glial Ephrin A3 regulates hippocampal dendritic spine morphology and glutamate transport
    Proceedings of the National Academy of Sciences of the United States of America, 2009
    Co-Authors: Maria A Carmona, Keith K Murai, Lei Wang, Amanda J Roberts, Elena B. Pasquale
    Abstract:

    Increasing evidence indicates the importance of neuron-glia communication for synaptic function, but the mechanisms involved are not fully understood. We reported that the EphA4 receptor tyrosine kinase is in dendritic spines of pyramidal neurons of the adult hippocampus and regulates spine morphology. We now show that the Ephrin-A3 ligand, which is located in the perisynaptic processes of astrocytes, is essential for maintaining EphA4 activation and normal spine morphology in vivo. Ephrin-A3-knockout mice have spine irregularities similar to those observed in EphA4-knockout mice. Remarkably, loss of Ephrin-A3 or EphA4 increases the expression of glial glutamate transporters. Consistent with this, glutamate transport is elevated in Ephrin-A3-null hippocampal slices whereas Eph-dependent stimulation of Ephrin-A3 signaling inhibits glutamate transport. Furthermore, some forms of hippocampus-dependent learning are impaired in the Ephrin-A3-knockout mice. Our results suggest that the interaction between neuronal EphA4 and glial Ephrin-A3 bidirectionally controls synapse morphology and glial glutamate transport, ultimately regulating hippocampal function.

  • heparan sulfate regulates Ephrin A3 epha receptor signaling
    Proceedings of the National Academy of Sciences of the United States of America, 2008
    Co-Authors: Fumitoshi Irie, Elena B. Pasquale, Misako Okuno, Kazu Matsumoto, Yu Yamaguchi
    Abstract:

    Increasing evidence indicates that many signaling pathways involve not only ligands and receptors but also various types of coreceptors and matrix components as additional layers of regulation. Signaling by Eph receptors and their Ephrin ligands plays a key role in a variety of biological processes, such as axon guidance and topographic map formation, synaptic plasticity, angiogenesis, and cancer. Little is known about whether the Ephrin-Eph receptor signaling system is subject to such additional layers of regulation. Here, we show that Ephrin-A3 binds to heparan sulfate, and that the presence of cell surface heparan sulfate is required for the full biological activity of Ephrin-A3. Among the Ephrins tested, including Ephrin-A1, -A2, -A5, -B1, and -B2, only Ephrin-A3 binds heparin or heparan sulfate. Ephrin-A3-dependent EphA receptor activation is reduced in mutant cells that are defective in heparan sulfate synthesis, in wild-type cells from which cell surface heparan sulfate has been removed, and in the hippocampus of conditional knockout mice defective in heparan sulfate synthesis. Ephrin-A3-dependent cell rounding is impaired in CHO cells lacking heparan sulfate, and cortical neurons lacking heparan sulfate exhibit impaired growth cone collapse. In contrast, cell rounding and growth cone collapse in response to Ephrin-A5, which does not bind heparan sulfate, are not affected by the absence of heparan sulfate. These results show that heparan sulfate modulates Ephrin/Eph signaling and suggest a physiological role for heparan sulfate proteoglycans in the regulation of Ephrin-A3-dependent biological processes.

  • control of hippocampal dendritic spine morphology through Ephrin A3 epha4 signaling
    Nature Neuroscience, 2003
    Co-Authors: Keith K Murai, Louis N Nguyen, Fumitoshi Irie, Elena B. Pasquale, Yu Yamaguchi
    Abstract:

    Communication between glial cells and neurons is emerging as a critical parameter of synaptic function. However, the molecular mechanisms underlying the ability of glial cells to modify synaptic structure and physiology are poorly understood. Here we describe a repulsive interaction that regulates postsynaptic morphology through the EphA4 receptor tyrosine kinase and its ligand Ephrin-A3. EphA4 is enriched on dendritic spines of pyramidal neurons in the adult mouse hippocampus, and Ephrin-A3 is localized on astrocytic processes that envelop spines. Activation of EphA4 by Ephrin-A3 was found to induce spine retraction, whereas inhibiting Ephrin/EphA4 interactions distorted spine shape and organization in hippocampal slices. Furthermore, spine irregularities in pyramidal neurons from EphA4 knockout mice and in slices transfected with kinase-inactive EphA4 indicated that Ephrin/EphA4 signaling is critical for spine morphology. Thus, our data support a model in which transient interactions between the Ephrin-A3 ligand and the EphA4 receptor regulate the structure of excitatory synaptic connections through neuroglial cross-talk.

Dong Feng Chen - One of the best experts on this subject based on the ideXlab platform.

  • Ephrin-A2 and -A3 are negative regulators of the regenerative potential of Möller cells.
    Chinese medical journal, 2014
    Co-Authors: Ruilin Zhu, Dong Feng Chen, Kin-sang Cho, Liu Yang
    Abstract:

    Background In a previous study, we demonstrated that Ephrin-A2 and -A3 negatively regulate the growth of neural progenitor cells in the central nervous system. Adult mice deficient in Ephrin-A2 and -A3 (A2(-/-)A3(-/-)) displayed active ongoing neurogenesis throughout the brain, and mice deficient in Ephrin-A3 alone showed increased proliferation of ciliary epithelium derived retinal stem cells. This study aimed to detect that the increase in proliferation and neurogenic potential of Muller cells is influenced by the absence of Ephrin-A2 and -A3. Methods We assessed the retinal and Muller cell expression of Ephrin-As and their receptor and neural progenitor cell markers by immunostaining and real-time PCR. We cultured purified primary Muller cells derived from wild-type and A2(-/-)A3(-/-) mice in a defined culture medium that enables trans-differentiation of Muller cells into retinal neurons. To evaluate proliferating Muller cells in vivo, we injected 5'-ethylnyl-2'-deoxiuridine (EdU) intraperitoneally to adult mice. Results Expression of Ephrin-A2/A3 and their receptor EphA4 were detected in the retinas of adult mice, with EphA4 expression particularly enriched in Muller cells. Muller cells of A2(-/-)A3(-/-) mice exhibited significantly elevated expression of retinal progenitor cell markers, Pax6 and Chx10, when compared with those from wild-type mice. Moreover, a higher percentage of Muller cells of A2(-/-)A3(-/-) mice trans-differentiated and became recoverin+ and β-III-tublin+ in the culture than those from wild type mice. Strikingly, an increased number of EdU+ retinal cells was detected in the retinas of adult A2(-/-)A3(-/-) mice as compared with wild-type mice. Conclusions Ephrin-A2 and -A3 are negative regulators of the proliferative and neurogenic potentials of Muller cells. Manipulating Ephrin-A signaling may thus represent a novel strategy for stimulating neuroregeneration from endogenous progenitors to participate in retinal repair in case of disease or damage.

  • Ephrin A3 suppresses wnt signaling to control retinal stem cell potency
    Stem Cells, 2013
    Co-Authors: Yuan Fang, Kin-sang Cho, Kissaou Tchedre, Seung-woo Lee, Chenying Guo, Hikaru Kinouchi, Shelley I. Fried, Xinghuai Sun, Dong Feng Chen
    Abstract:

    The ciliary epithelium (CE) of adult mammals has been reported to provide a source of retinal stem cells (RSCs) that can give rise to all retinal cell types in vitro. A recent study, however, suggests that CE-derived cells possess properties of pigmented ciliary epithelial cells and display little neurogenic potential. Here we show that the neurogenic potential of CE-derived cells is negatively regulated by Ephrin-A3, which is upregulated in the CE of postnatal mice and presents a strong prohibitory niche for adult RSCs. Addition of Ephrin-A3 inhibits proliferation of CE-derived RSCs and increases pigment 349 cell 359. In contrast, absence of Ephrin-A3 promotes proliferation and increases expression of neural progenitor cell markers and photoreceptor progeny. The negative effects of Ephrin-A3 on CE-derived RSCs are mediated through activation of an EphA4 receptor and suppression of Wnt3a/β-catenin signaling. Together, our data suggest that CE-derived RSCs contain the intrinsic machinery to generate photoreceptors and other retinal neurons, while the CE of adult mice expresses negative regulators that prohibit the proliferation and neural differentiation of RSCs. Manipulating Ephrin and Wnt/β-catenin signaling may, thus, represent a viable approach in activating the endogenous neurogenic potential of CE-derived RSCs for treating photoreceptor damage and retinal degenerative disorders. STEM CELLS2013;31:349–359

  • Ephrin A3 suppresses wnt signaling to control retinal stem cell potency
    Stem Cells, 2013
    Co-Authors: Yuan Fang, Kin-sang Cho, Kissaou Tchedre, Seung-woo Lee, Chenying Guo, Hikaru Kinouchi, Shelley I. Fried, Xinghuai Sun, Dong Feng Chen
    Abstract:

    The ciliary epithelium (CE) of adult mammals has been reported to provide a source of retinal stem cells (RSCs) that can give rise to all retinal cell types in vitro. A recent study, however, suggests that CE-derived cells possess properties of pigmented ciliary epithelial cells and display little neurogenic potential. Here we show that the neurogenic potential of CE-derived cells is negatively regulated by Ephrin-A3, which is upregulated in the CE of postnatal mice and presents a strong prohibitory niche for adult RSCs. Addition of Ephrin-A3 inhibits proliferation of CE-derived RSCs and increases pigment 349 cell 359. In contrast, absence of Ephrin-A3 promotes proliferation and increases expression of neural progenitor cell markers and photoreceptor progeny. The negative effects of Ephrin-A3 on CE-derived RSCs are mediated through activation of an EphA4 receptor and suppression of Wnt3a/β-catenin signaling. Together, our data suggest that CE-derived RSCs contain the intrinsic machinery to generate photoreceptors and other retinal neurons, while the CE of adult mice expresses negative regulators that prohibit the proliferation and neural differentiation of RSCs. Manipulating Ephrin and Wnt/β-catenin signaling may, thus, represent a viable approach in activating the endogenous neurogenic potential of CE-derived RSCs for treating photoreceptor damage and retinal degenerative disorders.

Yuan Fang - One of the best experts on this subject based on the ideXlab platform.

  • Ephrin A3 suppresses wnt signaling to control retinal stem cell potency
    Stem Cells, 2013
    Co-Authors: Yuan Fang, Kin-sang Cho, Kissaou Tchedre, Seung-woo Lee, Chenying Guo, Hikaru Kinouchi, Shelley I. Fried, Xinghuai Sun, Dong Feng Chen
    Abstract:

    The ciliary epithelium (CE) of adult mammals has been reported to provide a source of retinal stem cells (RSCs) that can give rise to all retinal cell types in vitro. A recent study, however, suggests that CE-derived cells possess properties of pigmented ciliary epithelial cells and display little neurogenic potential. Here we show that the neurogenic potential of CE-derived cells is negatively regulated by Ephrin-A3, which is upregulated in the CE of postnatal mice and presents a strong prohibitory niche for adult RSCs. Addition of Ephrin-A3 inhibits proliferation of CE-derived RSCs and increases pigment 349 cell 359. In contrast, absence of Ephrin-A3 promotes proliferation and increases expression of neural progenitor cell markers and photoreceptor progeny. The negative effects of Ephrin-A3 on CE-derived RSCs are mediated through activation of an EphA4 receptor and suppression of Wnt3a/β-catenin signaling. Together, our data suggest that CE-derived RSCs contain the intrinsic machinery to generate photoreceptors and other retinal neurons, while the CE of adult mice expresses negative regulators that prohibit the proliferation and neural differentiation of RSCs. Manipulating Ephrin and Wnt/β-catenin signaling may, thus, represent a viable approach in activating the endogenous neurogenic potential of CE-derived RSCs for treating photoreceptor damage and retinal degenerative disorders. STEM CELLS2013;31:349–359

  • Ephrin A3 suppresses wnt signaling to control retinal stem cell potency
    Stem Cells, 2013
    Co-Authors: Yuan Fang, Kin-sang Cho, Kissaou Tchedre, Seung-woo Lee, Chenying Guo, Hikaru Kinouchi, Shelley I. Fried, Xinghuai Sun, Dong Feng Chen
    Abstract:

    The ciliary epithelium (CE) of adult mammals has been reported to provide a source of retinal stem cells (RSCs) that can give rise to all retinal cell types in vitro. A recent study, however, suggests that CE-derived cells possess properties of pigmented ciliary epithelial cells and display little neurogenic potential. Here we show that the neurogenic potential of CE-derived cells is negatively regulated by Ephrin-A3, which is upregulated in the CE of postnatal mice and presents a strong prohibitory niche for adult RSCs. Addition of Ephrin-A3 inhibits proliferation of CE-derived RSCs and increases pigment 349 cell 359. In contrast, absence of Ephrin-A3 promotes proliferation and increases expression of neural progenitor cell markers and photoreceptor progeny. The negative effects of Ephrin-A3 on CE-derived RSCs are mediated through activation of an EphA4 receptor and suppression of Wnt3a/β-catenin signaling. Together, our data suggest that CE-derived RSCs contain the intrinsic machinery to generate photoreceptors and other retinal neurons, while the CE of adult mice expresses negative regulators that prohibit the proliferation and neural differentiation of RSCs. Manipulating Ephrin and Wnt/β-catenin signaling may, thus, represent a viable approach in activating the endogenous neurogenic potential of CE-derived RSCs for treating photoreceptor damage and retinal degenerative disorders.

Kin-sang Cho - One of the best experts on this subject based on the ideXlab platform.

  • Ephrin-A2 and -A3 are negative regulators of the regenerative potential of Möller cells.
    Chinese medical journal, 2014
    Co-Authors: Ruilin Zhu, Dong Feng Chen, Kin-sang Cho, Liu Yang
    Abstract:

    Background In a previous study, we demonstrated that Ephrin-A2 and -A3 negatively regulate the growth of neural progenitor cells in the central nervous system. Adult mice deficient in Ephrin-A2 and -A3 (A2(-/-)A3(-/-)) displayed active ongoing neurogenesis throughout the brain, and mice deficient in Ephrin-A3 alone showed increased proliferation of ciliary epithelium derived retinal stem cells. This study aimed to detect that the increase in proliferation and neurogenic potential of Muller cells is influenced by the absence of Ephrin-A2 and -A3. Methods We assessed the retinal and Muller cell expression of Ephrin-As and their receptor and neural progenitor cell markers by immunostaining and real-time PCR. We cultured purified primary Muller cells derived from wild-type and A2(-/-)A3(-/-) mice in a defined culture medium that enables trans-differentiation of Muller cells into retinal neurons. To evaluate proliferating Muller cells in vivo, we injected 5'-ethylnyl-2'-deoxiuridine (EdU) intraperitoneally to adult mice. Results Expression of Ephrin-A2/A3 and their receptor EphA4 were detected in the retinas of adult mice, with EphA4 expression particularly enriched in Muller cells. Muller cells of A2(-/-)A3(-/-) mice exhibited significantly elevated expression of retinal progenitor cell markers, Pax6 and Chx10, when compared with those from wild-type mice. Moreover, a higher percentage of Muller cells of A2(-/-)A3(-/-) mice trans-differentiated and became recoverin+ and β-III-tublin+ in the culture than those from wild type mice. Strikingly, an increased number of EdU+ retinal cells was detected in the retinas of adult A2(-/-)A3(-/-) mice as compared with wild-type mice. Conclusions Ephrin-A2 and -A3 are negative regulators of the proliferative and neurogenic potentials of Muller cells. Manipulating Ephrin-A signaling may thus represent a novel strategy for stimulating neuroregeneration from endogenous progenitors to participate in retinal repair in case of disease or damage.

  • Ephrin A3 suppresses wnt signaling to control retinal stem cell potency
    Stem Cells, 2013
    Co-Authors: Yuan Fang, Kin-sang Cho, Kissaou Tchedre, Seung-woo Lee, Chenying Guo, Hikaru Kinouchi, Shelley I. Fried, Xinghuai Sun, Dong Feng Chen
    Abstract:

    The ciliary epithelium (CE) of adult mammals has been reported to provide a source of retinal stem cells (RSCs) that can give rise to all retinal cell types in vitro. A recent study, however, suggests that CE-derived cells possess properties of pigmented ciliary epithelial cells and display little neurogenic potential. Here we show that the neurogenic potential of CE-derived cells is negatively regulated by Ephrin-A3, which is upregulated in the CE of postnatal mice and presents a strong prohibitory niche for adult RSCs. Addition of Ephrin-A3 inhibits proliferation of CE-derived RSCs and increases pigment 349 cell 359. In contrast, absence of Ephrin-A3 promotes proliferation and increases expression of neural progenitor cell markers and photoreceptor progeny. The negative effects of Ephrin-A3 on CE-derived RSCs are mediated through activation of an EphA4 receptor and suppression of Wnt3a/β-catenin signaling. Together, our data suggest that CE-derived RSCs contain the intrinsic machinery to generate photoreceptors and other retinal neurons, while the CE of adult mice expresses negative regulators that prohibit the proliferation and neural differentiation of RSCs. Manipulating Ephrin and Wnt/β-catenin signaling may, thus, represent a viable approach in activating the endogenous neurogenic potential of CE-derived RSCs for treating photoreceptor damage and retinal degenerative disorders. STEM CELLS2013;31:349–359

  • Ephrin A3 suppresses wnt signaling to control retinal stem cell potency
    Stem Cells, 2013
    Co-Authors: Yuan Fang, Kin-sang Cho, Kissaou Tchedre, Seung-woo Lee, Chenying Guo, Hikaru Kinouchi, Shelley I. Fried, Xinghuai Sun, Dong Feng Chen
    Abstract:

    The ciliary epithelium (CE) of adult mammals has been reported to provide a source of retinal stem cells (RSCs) that can give rise to all retinal cell types in vitro. A recent study, however, suggests that CE-derived cells possess properties of pigmented ciliary epithelial cells and display little neurogenic potential. Here we show that the neurogenic potential of CE-derived cells is negatively regulated by Ephrin-A3, which is upregulated in the CE of postnatal mice and presents a strong prohibitory niche for adult RSCs. Addition of Ephrin-A3 inhibits proliferation of CE-derived RSCs and increases pigment 349 cell 359. In contrast, absence of Ephrin-A3 promotes proliferation and increases expression of neural progenitor cell markers and photoreceptor progeny. The negative effects of Ephrin-A3 on CE-derived RSCs are mediated through activation of an EphA4 receptor and suppression of Wnt3a/β-catenin signaling. Together, our data suggest that CE-derived RSCs contain the intrinsic machinery to generate photoreceptors and other retinal neurons, while the CE of adult mice expresses negative regulators that prohibit the proliferation and neural differentiation of RSCs. Manipulating Ephrin and Wnt/β-catenin signaling may, thus, represent a viable approach in activating the endogenous neurogenic potential of CE-derived RSCs for treating photoreceptor damage and retinal degenerative disorders.

Seung-woo Lee - One of the best experts on this subject based on the ideXlab platform.

  • Ephrin A3 suppresses wnt signaling to control retinal stem cell potency
    Stem Cells, 2013
    Co-Authors: Yuan Fang, Kin-sang Cho, Kissaou Tchedre, Seung-woo Lee, Chenying Guo, Hikaru Kinouchi, Shelley I. Fried, Xinghuai Sun, Dong Feng Chen
    Abstract:

    The ciliary epithelium (CE) of adult mammals has been reported to provide a source of retinal stem cells (RSCs) that can give rise to all retinal cell types in vitro. A recent study, however, suggests that CE-derived cells possess properties of pigmented ciliary epithelial cells and display little neurogenic potential. Here we show that the neurogenic potential of CE-derived cells is negatively regulated by Ephrin-A3, which is upregulated in the CE of postnatal mice and presents a strong prohibitory niche for adult RSCs. Addition of Ephrin-A3 inhibits proliferation of CE-derived RSCs and increases pigment 349 cell 359. In contrast, absence of Ephrin-A3 promotes proliferation and increases expression of neural progenitor cell markers and photoreceptor progeny. The negative effects of Ephrin-A3 on CE-derived RSCs are mediated through activation of an EphA4 receptor and suppression of Wnt3a/β-catenin signaling. Together, our data suggest that CE-derived RSCs contain the intrinsic machinery to generate photoreceptors and other retinal neurons, while the CE of adult mice expresses negative regulators that prohibit the proliferation and neural differentiation of RSCs. Manipulating Ephrin and Wnt/β-catenin signaling may, thus, represent a viable approach in activating the endogenous neurogenic potential of CE-derived RSCs for treating photoreceptor damage and retinal degenerative disorders. STEM CELLS2013;31:349–359

  • Ephrin A3 suppresses wnt signaling to control retinal stem cell potency
    Stem Cells, 2013
    Co-Authors: Yuan Fang, Kin-sang Cho, Kissaou Tchedre, Seung-woo Lee, Chenying Guo, Hikaru Kinouchi, Shelley I. Fried, Xinghuai Sun, Dong Feng Chen
    Abstract:

    The ciliary epithelium (CE) of adult mammals has been reported to provide a source of retinal stem cells (RSCs) that can give rise to all retinal cell types in vitro. A recent study, however, suggests that CE-derived cells possess properties of pigmented ciliary epithelial cells and display little neurogenic potential. Here we show that the neurogenic potential of CE-derived cells is negatively regulated by Ephrin-A3, which is upregulated in the CE of postnatal mice and presents a strong prohibitory niche for adult RSCs. Addition of Ephrin-A3 inhibits proliferation of CE-derived RSCs and increases pigment 349 cell 359. In contrast, absence of Ephrin-A3 promotes proliferation and increases expression of neural progenitor cell markers and photoreceptor progeny. The negative effects of Ephrin-A3 on CE-derived RSCs are mediated through activation of an EphA4 receptor and suppression of Wnt3a/β-catenin signaling. Together, our data suggest that CE-derived RSCs contain the intrinsic machinery to generate photoreceptors and other retinal neurons, while the CE of adult mice expresses negative regulators that prohibit the proliferation and neural differentiation of RSCs. Manipulating Ephrin and Wnt/β-catenin signaling may, thus, represent a viable approach in activating the endogenous neurogenic potential of CE-derived RSCs for treating photoreceptor damage and retinal degenerative disorders.