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Renping Zhou - One of the best experts on this subject based on the ideXlab platform.
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decreased maternal behavior and anxiety in Ephrin A5 mice
Genes Brain and Behavior, 2017Co-Authors: Michal Sheleg, Renping Zhou, George C. Wagner, Alexander W. KusnecovAbstract:During development of the nervous system, molecular signals mediating cell-cell interactions play critical roles in the guidance of axonal growth and establishment of synaptic functions. The Eph family of tyrosine kinase receptors and their Ephrin ligands has been shown to mediate neuronal interactions in the development of topographic axon projection maps in several brain regions, and the loss of Eph activities result in defects in select axonal pathways. However, effects of deficiencies of the Eph signals on animal behavior have not been well documented. In this study, we showed that inactivation of a ligand of the Eph receptors, Ephrin-A5, resulted in defects in maternal behavior and alterations in anxiety. Female Ephrin-A5-/- mice show significant defects in nest building and pup retrieval. In addition, lower levels of anxiety were observed in both male and female null mice. These changes were not due to deficiencies in estradiol, progesterone, or corticosterone levels. Our observations suggest that Ephrin-A5 plays a key role in the development and/or function of neural pathways mediating mouse maternal care and anxiety.
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Decreased maternal behavior and anxiety in Ephrin-A5-/- mice.
Genes brain and behavior, 2016Co-Authors: Michal Sheleg, George C. Wagner, Alexander W. Kusnecov, Renping ZhouAbstract:During development of the nervous system, molecular signals mediating cell-cell interactions play critical roles in the guidance of axonal growth and establishment of synaptic functions. The Eph family of tyrosine kinase receptors and their Ephrin ligands has been shown to mediate neuronal interactions in the development of topographic axon projection maps in several brain regions, and the loss of Eph activities result in defects in select axonal pathways. However, effects of deficiencies of the Eph signals on animal behavior have not been well documented. In this study, we showed that inactivation of a ligand of the Eph receptors, Ephrin-A5, resulted in defects in maternal behavior and alterations in anxiety. Female Ephrin-A5-/- mice show significant defects in nest building and pup retrieval. In addition, lower levels of anxiety were observed in both male and female null mice. These changes were not due to deficiencies in estradiol, progesterone, or corticosterone levels. Our observations suggest that Ephrin-A5 plays a key role in the development and/or function of neural pathways mediating mouse maternal care and anxiety.
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Ephrin-A5 Is Required for Optimal Fertility and a Complete Ovulatory Response to Gonadotropins in the Female Mouse
Endocrinology, 2015Co-Authors: Adrian Buensuceso, Renping Zhou, Alexander I. Son, Marilène Paquet, Benjamin M. Withers, Bonnie J. DerooAbstract:Follicle growth and ovulation involve the coordinated expression of many genes, driven by FSH and LH. Reports indicate that Eph receptors and Ephrins are expressed in the ovary, suggesting roles in follicle growth and/or ovulation. We previously reported FSH-induced expression of Ephrin-A5 (EFNA5) and 4 of its cognate Eph receptors in mouse granulosa cells. We now report that female mice lacking EFNA5 are subfertile, exhibit a compromised response to LH, and display abnormal ovarian histology after superovulation. EfnA5(-/-) females litters were 40% smaller than controls, although no difference in litter frequency was detected. The ovarian response to superovulation was also compromised in EfnA5(-/-) females, with 37% fewer oocytes ovulated than controls. These results corresponded with a reduction in ovarian mRNA levels of several LH-responsive genes, including Pgr, Ptgs2, Tnfaip6, Ereg, Btc, and Adamts4, suggesting that EfnA5(-/-) ovaries exhibit a partially attenuated response to LH. Histopathological analysis indicated that superovulated EfnA5(-/-) females exhibited numerous ovarian defects, including intraovarian release of cumulus oocyte complexes, increased incidence of oocytes trapped within luteinized follicles, granulosa cell and follicular fluid emboli, fibrin thrombi, and interstitial hemorrhage. In addition, adult EfnA5(-/-) ovaries exhibited a 4-fold increase in multioocyte follicles compared with controls, although no difference was detected in 3-week-old mice, suggesting the possibility of follicle merging. Our observations indicate that loss of EFNA5 in female mice results in subfertility and imply that Eph-Ephrin signaling may also play a previously unidentified role in the regulation of fertility in women.
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Breakdown of interlocking domains may contribute to formation of membranous globules and lens opacity in Ephrin-A5−/− mice
Experimental eye research, 2015Co-Authors: Sondip K. Biswas, Alexander I. Son, Renping ZhouAbstract:Ephrin-A5, a ligand of the Eph family of receptor tyrosine kinases, plays a key role in lens fiber cell packing and cell-cell adhesion, with approximately 87% of Ephrin-A5(-/-) mice develop nuclear cataracts. Here, we investigated the extensive formation of light-scattering globules associated with breakdown of interlocking protrusions during lens opacification in Ephrin-A5(-/-) mice. Lenses from wild-type (WT) and Ephrin-A5(-/-) mice between 2 and 21 weeks old were studied with light and electron microscopy, immunofluorescence labeling, freeze-fracture TEM and filipin cytochemistry for membrane cholesterol detection. Lens opacities with various densities were first observed in Ephrin-A5(-/-) mice at around 60 days old. Dense cataracts in the mutant lenses were seen primarily in the nuclear region surrounded by transparent cortices from all eyes examined. We confirmed that a majority of nuclear cataracts were dislocated posteriorly and ruptured the thinner posterior lens capsule. SEM analysis indicated that numerous interlocking protrusions and wavy ridge-and-valley membrane surfaces in deep cortical and nuclear fibers did not cause lens opacity in both transparent Ephrin-A5(-/-) and WT mice. In contrast, abundant isolated membranous globules of approximately 1000 nm in size were distributed randomly along the intact fiber cells during early stage of all Ephrin-A5(-/-) cataracts examined. A further examination using both SEM and TEM revealed that isolated globules were generated from the disintegrated interlocking protrusions originally located along the corners of hexagonal fiber cells. Freeze-fracture TEM further revealed the association of square-array aquaporin junctions with both isolated globules and interlocking membrane domains. This study reports for the first time that disrupted interlocking protrusions are the source of numerous large membranous globules that contribute to light scattering and nuclear cataracts in the Ephrin-A5(-/-) mice. Our results further suggest that dissociations of N-cadherin and adherens junctions in the associated interlocking domains may result in the formation of isolated globules and nuclear opacities in the Ephrin-A5(-/-) mice.
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Ephrin-A5 regulates inter-male aggression in mice
Behavioural brain research, 2015Co-Authors: Michal Sheleg, Carrie L. Yochum, George C. Wagner, Jason R Richardson, Renping ZhouAbstract:The Eph family of receptor tyrosine kinases play key roles in both the patterning of the developing nervous system and neural plasticity in the mature brain. To determine functions of Ephrin-A5, a GPI-linked ligand to the Eph receptors, in animal behavior regulations, we examined effects of its inactivation on male mouse aggression. When tested in the resident-intruder paradigm for offensive aggression, Ephrin-A5-mutant animals (Ephrin-A5−/−) exhibited severe reduction in conspecific aggression compared to wild-type controls. On the contrary, defensive aggression in the form of target biting was higher in Ephrin-A5−/− mice, indicating that the mutant mice are capable of attacking behavior. In addition, given the critical role of olfaction in aggressive behavior, we examined the ability of the Ephrin-A5−/− mice to smell and found no differences between the mutant and control animals. Testosterone levels in the mutant mice were also found to be within the normal range. Taken together, our data reveal a new role of Ephrin-A5 in the regulation of aggressive behavior in mice.
Margaret A. Cooper - One of the best experts on this subject based on the ideXlab platform.
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Formation of persistent hyperplastic primary vitreous in Ephrin-A5-/- mice.
Investigative ophthalmology & visual science, 2014Co-Authors: Alexander I. Son, Michal Sheleg, Margaret A. Cooper, Yuhai Sun, Norman J. Kleiman, Renping ZhouAbstract:PURPOSE Primary vitreous regression is a critical event in mammalian eye development required for proper ocular maturity and unhindered vision. Failure of this event results in the eye disease persistent hyperplastic primary vitreous (PHPV), also identified as persistent fetal vasculature (PFV), a condition characterized by the presence of a fibrovascular mass adjacent to the lens and retina, and associated with visual disability and blindness. Here, we identify Ephrin-A5 to be a critical regulator for primary vitreous regression. METHODS Wild-type and Ephrin-A5(-/-) eyes were examined at various developmental stages to determine the progression of PHPV. Eye tissue was sectioned and examined by H&E staining. Protein expression and localization was determined through immunohistochemistry. Relative levels of Eph receptors were determined by RT-PCR. RESULTS Ephrin-A5(-/-) animals develop ocular phenotypes representative of PHPV, most notably the presence of a large hyperplastic mass posterior to the lens that remains throughout the lifetime of the animal. The aberrant tissue in these mutant mice consists of residual hyaloid vessels surrounded by pigmented cells of neural crest origin. Labeling with bromodeoxyuridine (BrdU) and detection of proliferating cell nuclear antigen (PCNA) expression shows that the mass in Ephrin-A5(-/-) animals is mitotically active in embryonic and postnatal stages. CONCLUSIONS Ephrin-A5 is a critical factor that regulates primary vitreous regression.
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formation of persistent hyperplastic primary vitreous in Ephrin A5 mice
Investigative Ophthalmology & Visual Science, 2014Co-Authors: Alexander I. Son, Michal Sheleg, Margaret A. Cooper, Yuhai Sun, Norman J. Kleiman, Renping ZhouAbstract:PURPOSE Primary vitreous regression is a critical event in mammalian eye development required for proper ocular maturity and unhindered vision. Failure of this event results in the eye disease persistent hyperplastic primary vitreous (PHPV), also identified as persistent fetal vasculature (PFV), a condition characterized by the presence of a fibrovascular mass adjacent to the lens and retina, and associated with visual disability and blindness. Here, we identify Ephrin-A5 to be a critical regulator for primary vitreous regression. METHODS Wild-type and Ephrin-A5(-/-) eyes were examined at various developmental stages to determine the progression of PHPV. Eye tissue was sectioned and examined by H&E staining. Protein expression and localization was determined through immunohistochemistry. Relative levels of Eph receptors were determined by RT-PCR. RESULTS Ephrin-A5(-/-) animals develop ocular phenotypes representative of PHPV, most notably the presence of a large hyperplastic mass posterior to the lens that remains throughout the lifetime of the animal. The aberrant tissue in these mutant mice consists of residual hyaloid vessels surrounded by pigmented cells of neural crest origin. Labeling with bromodeoxyuridine (BrdU) and detection of proliferating cell nuclear antigen (PCNA) expression shows that the mass in Ephrin-A5(-/-) animals is mitotically active in embryonic and postnatal stages. CONCLUSIONS Ephrin-A5 is a critical factor that regulates primary vitreous regression.
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Further analysis of the lens of Ephrin-A5−/− mice: development of postnatal defects
Molecular vision, 2013Co-Authors: Alexander I. Son, Michal Sheleg, Margaret A. Cooper, Yuhai Sun, Norman J. Kleiman, Renping ZhouAbstract:Purpose The cells of the mammalian lens must be carefully organized and regulated to maintain clarity. Recent studies have identified the Eph receptor ligand Ephrin-A5 as a major contributor to lens development, as mice lacking Ephrin-A5 develop abnormal lenses, resulting in cataracts. As a follow-up to our previous study on the cataracts observed in Ephrin-A5−/− animals, we have further examined the morphological and molecular changes in the Ephrin-A5−/− lens.
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Ephrin-A5 regulates the formation of the ascending midbrain dopaminergic pathways
Developmental neurobiology, 2009Co-Authors: Margaret A. Cooper, Kazuto Kobayashi, Renping ZhouAbstract:Dopaminergic neurons from the substantia nigra and the ventral tegmental area of the midbrain project to the caudate/putamen and nucleus accumbens, respectively, establishing the mesostriatal and the mesolimbic pathways. However, the mechanisms underlying the development of these pathways are not well understood. In the current study, the EphA5 receptor and its corresponding ligand, Ephrin-A5, were shown to regulate dopaminergic axon outgrowth and influence the formation of the midbrain dopaminergic pathways. Using a strain of mutant mice in which the EphA5 cytoplasmic domain was replaced with β-galactosidase, EphA5 protein expression was detected in both the ventral tegmental area and the substantia nigra of the midbrain. Ephrin-A5 was found in both the dorsolateral and the ventromedial regions of the striatum, suggesting a role in mediating dopaminergic axon-target interactions. In the presence of Ephrin-A5, dopaminergic neurons extended longer neurites in in vitro coculture assays. Furthermore, in mice lacking Ephrin-A5, retrograde tracing studies revealed that fewer neurons sent axons to the striatum. These observations indicate that the interactions between Ephrin-A ligands and EphA receptors promote growth and targeting of the midbrain dopaminergic axons to the striatum. © 2008 Wiley Periodicals, Inc. Develop Neurobiol, 2009
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loss of Ephrin A5 function disrupts lens fiber cell packing and leads to cataract
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Margaret A. Cooper, Norman J. Kleiman, Daniel Komlos, Renping ZhouAbstract:Cell–cell interactions organize lens fiber cells into highly ordered structures to maintain transparency. However, signals regulating such interactions have not been well characterized. We report here that Ephrin-A5, a ligand of the Eph receptor tyrosine kinases, plays a key role in lens fiber cell shape and cell–cell interactions. Lens fiber cells in mice lacking Ephrin-A5 function appear rounded and irregular in cross-section, in contrast to their normal hexagonal appearance in WT lenses. Cataracts eventually develop in 87% of Ephrin-A5 KO mice. We further demonstrate that Ephrin-A5 interacts with the EphA2 receptor to regulate the adherens junction complex by enhancing recruitment of β-catenin to N-cadherin. These results indicate that the Eph receptors and their ligands are critical regulators of lens development and maintenance.
Jürgen Bolz - One of the best experts on this subject based on the ideXlab platform.
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Thalamic afferents influence cortical progenitors via Ephrin A5-EphA4 interactions
Development (Cambridge England), 2014Co-Authors: Katrin Gerstmann, Jürgen Bolz, Daniel Pensold, Judit Symmank, Mukhran Khundadze, Christian A. Hübner, Geraldine ZimmerAbstract:The phenotype of excitatory cerebral cortex neurons is specified at the progenitor level, orchestrated by various intrinsic and extrinsic factors. Here, we provide evidence for a subcortical contribution to cortical progenitor regulation by thalamic axons via Ephrin A5-EphA4 interactions. Ephrin A5 is expressed by thalamic axons and represents a high-affinity ligand for EphA4 receptors detected in cortical precursors. Recombinant Ephrin A5-Fc protein, as well as Ephrin A ligand-expressing, thalamic axons affect the output of cortical progenitor division in vitro. Ephrin A5-deficient mice show an altered division mode of radial glial cells (RGCs) accompanied by increased numbers of intermediate progenitor cells (IPCs) and an elevated neuronal production for the deep cortical layers at E13.5. In turn, at E16.5 the pool of IPCs is diminished, accompanied by reduced rates of generated neurons destined for the upper cortical layers. This correlates with extended infragranular layers at the expense of superficial cortical layers in adult Ephrin A5-deficient and EphA4-deficient mice. We suggest that Ephrin A5 ligands imported by invading thalamic axons interact with EphA4-expressing RGCs, thereby contributing to the fine-tuning of IPC generation and thus the proper neuronal output for cortical layers.
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Structural alterations of spiny stellate cells in the somatosensory cortex in Ephrin-A5-deficient mice.
The Journal of comparative neurology, 2009Co-Authors: Andre Guellmar, Judith Rudolph, Jürgen BolzAbstract:Previous studies demonstrated that in Ephrin-A5-deficient mice corticothalamic arbors are reduced by more than 50% in layer 4 of the somatosensory cortex (S1), where Ephrin-A5 is normally expressed. Here we examined possible consequences of the reduced thalamic input on spiny stellate cells, the target neurons of thalamocortical afferents. Using ballistic delivery of particles coated with lipophilic dyes in fixed slices and confocal laser-microscopy, we could quantitatively analyze the morphology of these neurons. Cells were examined in S1 at postnatal day 8 (P8), when thalamic afferents establish synaptic contacts and the dendrites of their target cells are covered with filopodia, and at P23, after synapse formation and replacement of filopodia by spines. Our results indicate that at P8 the dendrites of cells in mutant animals exhibit more filopodia and are more branched than dendrites of wildtype cells. In contrast, there is no difference in the extent of the dendritic tree between knockout and control animals. At P23, dendrites of neurons in Ephrin-A5-deficient mice are still more branched, but possess fewer spines than wildtype cells. Thus, at early stages layer 4 neurons appear to compensate the reduced thalamic input by increasing dendritic branching and the density of filopodia. However, while at later stages the dendrites of layer 4 neurons in mutants are still more branched, their spine density is now lower than in wildtype cells. Taken together, these data demonstrate that the structure of spiny stellate cells is shaped by thalamic input and Eph receptor signaling. J. Comp. Neurol. 517:645–654, 2009. © 2009 Wiley-Liss, Inc.
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Ephrin-A5 acts as a repulsive cue for migrating cortical interneurons.
The European journal of neuroscience, 2008Co-Authors: Geraldine Zimmer, Patricia P. Garcez, Judith Rudolph, Ronny Niehage, Franco Weth, Roberto Lent, Jürgen BolzAbstract:Cortical interneurons are born in the germinative zones of the ganglionic eminences in the subpallium, and migrate tangentially in spatially and temporally well-defined corridors into the neocortex. Because Ephrin-A5 is expressed in the ventricular zone (VZ) of the ganglionic eminences at these developmental stages, we examined the possible effects of this molecule on interneuron migration. Double-immunocytochemistry of dissociated neurons from the medial ganglionic eminences (MGE) revealed that calbindin-positive cells express the EphA4-receptor. In situ, EphA4 is strongly expressed in the subventricular zone of the ganglionic eminences. Using different in vitro assays, we found that Ephrin-A5 acts as a repellent cue for MGE neurons. We then examined interneuron migration in slice overlay experiments, where MGE-derived explants from enhanced green fluorescent protein-expressing transgenic mice were homotopically grafted into host slices from wild-type littermate embryos. In these in vitro preparations, interneurons recapitulated in vivo cell migration in several respects. However, interneurons in brain slices also migrated in the VZ of the ganglionic eminences, a region that is strictly avoided in vivo. In situ hybridizations revealed that Ephrin-A5 became downregulated in the VZ in vitro. When recombinant Ephrin-A5-Fc was added to the slices, it preferentially bound to the VZ, and migrating MGE neurons avoided the VZ as in vivo. The restoration of the normal migration pathway in slices required Ephrin-A5 clustering and signalling of Src family kinases. Together, these experiments suggest that Ephrin-A5 acts as an inhibitory flank that contributes to define the pathway of migrating interneurons.
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Ephrin-A5 promotes the formation of terminal thalamocortical arbors.
Neuroreport, 2008Co-Authors: Daniela Uziel, Sven Mühlfriedel, Jürgen BolzAbstract:Ephrins-A5 are expressed in the cortical target layer of thalamic afferents at the time when these axons form terminal arbors. Previous in-vitro studies provided evidence that Ephrin-A5 supports the branching of thalamic axons, but there is no direct in-vivo evidence for such a growth-promoting effect. Here we examined thalamocortical projections in Ephrins-A5 deficient mice. Our results demonstrate that the laminar specificity of thalamic afferents in Ephrin-A5 -/- mutants remains preserved, but axonal arbor formation is greatly reduced. Thus, Ephrin-A5 specifically regulates branch formation of thalamic axons, but does not affect target layer selection. Ephrin-A5-mutant mice are, therefore, a unique model to study the effects of reduced thalamic innervation on the assembly of cortical circuits and sensory processing.
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Multiple effects of Ephrin-A5 on cortical neurons are mediated by SRC family kinases.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2007Co-Authors: Geraldine Zimmer, Franco Weth, Bettina Kästner, Jürgen BolzAbstract:The Eph receptor tyrosine kinases and their membrane-bound ligands, the Ephrins, are involved in a variety of developmental processes such as axonal guidance, cell migration, cell adhesion, proliferation, and differentiation. In addition to repulsive effects, Ephrins can also induce attractive responses. Up to now, little was known about the underlying signaling mechanisms that regulate attractive versus repulsive effects. In this study, we show that Ephrin-A5 enhances the motility of cortical neurons that is dependent on the activity of Src-family kinases (SFKs). Ephrin-A5 further changes the adhesive properties of neurons by inducing the formation of cell aggregates. Using the stripe assay, we found that the motogenic effect of Ephrin-A5 is the result of repulsive Ephrin-A interactions. Blocking SFK function leads to a conversion of repulsion into adhesion, suggesting that SFKs can act as a biological switch for the response of EphA receptors. Finally, we discovered a ligand-induced release of membrane particles containing EphA receptors, suggesting membrane ripping as a novel mechanism to overcome the "Ephrin paradox" of repulsion after high-affinity receptor-ligand binding.
Jonas Frisén - One of the best experts on this subject based on the ideXlab platform.
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impaired hippocampal neurogenesis and vascular formation in Ephrin A5 deficient mice
Stem Cells, 2010Co-Authors: Yoshinobu Hara, Jonas Frisén, Tadashi Nomura, Kaichi Yoshizaki, Noriko OsumiAbstract:Neurogenesis occurs throughout the life in the mammalian brain. The hippocampal dentate gyrus (DG) is one of the major regions of the adult neurogenesis, where neural stem/progenitor cells continuously generate new granule neurons, although molecular mechanisms underlying generation and maintenance of newly born neurons are still elusive. Here we show that Ephrin-A5, a ligand for Eph receptor tyrosine kinases, plays multiple roles in both neurogenesis and vascular formation in the adult hippocampus. In mice lacking Ephrin-A5 function, cell proliferation and survival of newborn neurons were severely reduced in the hippocampus DG. Furthermore, Ephrin-A5-deficient mice exhibited altered distribution of EphA4 receptor in the vascular endothelial cells and increased narrower capillaries in the hippocampus DG. EphA/Ephrin-A signaling thus plays crucial roles in the establishment and/or maintenance of the brain vascular system, as an essential constituent of the adult neurogenic niche. STEM CELLS 2010;28:974–983
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Impaired Hippocampal Neurogenesis and Vascular Formation in Ephrin‐A5‐Deficient Mice
Stem cells (Dayton Ohio), 2010Co-Authors: Yoshinobu Hara, Jonas Frisén, Tadashi Nomura, Kaichi Yoshizaki, Noriko OsumiAbstract:Neurogenesis occurs throughout the life in the mammalian brain. The hippocampal dentate gyrus (DG) is one of the major regions of the adult neurogenesis, where neural stem/progenitor cells continuously generate new granule neurons, although molecular mechanisms underlying generation and maintenance of newly born neurons are still elusive. Here we show that Ephrin-A5, a ligand for Eph receptor tyrosine kinases, plays multiple roles in both neurogenesis and vascular formation in the adult hippocampus. In mice lacking Ephrin-A5 function, cell proliferation and survival of newborn neurons were severely reduced in the hippocampus DG. Furthermore, Ephrin-A5-deficient mice exhibited altered distribution of EphA4 receptor in the vascular endothelial cells and increased narrower capillaries in the hippocampus DG. EphA/Ephrin-A signaling thus plays crucial roles in the establishment and/or maintenance of the brain vascular system, as an essential constituent of the adult neurogenic niche. STEM CELLS 2010;28:974–983
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Ephrin-A5 modulates the topographic mapping and connectivity of commissural axons in murine hippocampus.
Neuroscience, 2006Co-Authors: Raquel Otal, Ferran Burgaya, Jonas Frisén, Eduardo Soriano, A. MartínezAbstract:Entorhinal and commissural/associational projections show a non-overlapping distribution in the hippocampus proper and the dentate gyrus. The expression of Ephrins and their Eph receptors in the developing hippocampus indicates that this family of axonal guidance molecules may modulate the formation of these connections. Here we focused on the role of the Ephrin-A5 ligand in the development of the main hippocampal afferents. In situ hybridization showed that Ephrin-A5 mRNA was detected mainly in the principal cells of the hippocampus proper and in the dentate gyrus throughout postnatal development. Immunocytochemical analyses revealed prominent expression of the EphA3 receptor, a putative receptor for Ephrin-A5, in the main cells and the neuropil of the developing hippocampus. Tracing experiments in Ephrin-A5(−/−) mice showed that commissural projections were transiently altered in the hippocampus proper at P5, but they were mistargeted throughout the postnatal development in the dentate gyrus. Immunocytochemistry with anti-calbindin antibodies revealed that the dentate mossy fiber projection was not altered in Ephrin-A5(−/−) mice. Electron microscopy studies showed alterations in the density of synapses and spines in commissural/associational layers, but not in entorhinal layers, and in the mossy fibers in these animals. Taken together, these findings indicate that Ephrin-A5 signaling is involved in the formation and maturation of synapses in the hippocampus.
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Pax6-dependent boundary defines alignment of migrating olfactory cortex neurons via the repulsive activity of Ephrin A5.
Development (Cambridge England), 2006Co-Authors: Tadashi Nomura, Jonas Frisén, Johan Holmberg, Noriko OsumiAbstract:Neuronal migration is a prerequisite event for the establishment of highly ordered neuronal circuits in the developing brain. Here, we report Pax6-dependent alignment of the olfactory cortex neurons in the developing telencephalon. These neurons were generated in the dorsal part of telencephalon, migrated ventrally and stopped at the pallium-subpallium boundary (PSB). In Pax6 mutant rat embryos, however, these neurons invaded the ventral part of the telencephalon by crossing the PSB. Ephrin A5, one of the ligands for EphA receptors, was specifically expressed in the ventral part of the telencephalon, and its expression level was markedly reduced in the Pax6 mutant. Gain- and loss-of-function studies of Ephrin A5 indicated that Ephrin A5 plays an important role in the alignment of olfactory cortex neurons at the PSB. Our results suggest that Pax6-regulated Ephrin A5 acts as a repulsive molecule for olfactory cortex neurons in the developing telencephalon.
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Malformation of the Functional Organization of Somatosensory Cortex in Adult Ephrin-A5 Knock-Out Mice Revealed by In Vivo Functional Imaging
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2000Co-Authors: Neal Prakash, Jonas Frisén, Pierre Vanderhaeghen, Susana Cohen-cory, John G. Flanagan, Ron D. FrostigAbstract:The molecular mechanisms that coordinate the functional organization of the mammalian neocortex are largely unknown. We tested the involvement of a putative guidance label, Ephrin-A5, in the functional organization of the somatosensory cortex by quantifying the functional representations of individual whiskers in vivo in adult Ephrin-A5 knock-out mice, using intrinsic signal optical imaging. In wild-type mice Ephrin-A5 is expressed in a gradient in the somatosensory cortex during development. In adult Ephrin-A5 knock-out mice, we found a spatial gradient of change in the amount of cortical territory shared by individual whisker functional representations across the somatosensory cortex, as well as a gradient of change in the distance between the functional representations. Both gradients of change were in correspondence with the developmental expression gradient of Ephrin-A5 in wild-type mice. These changes involved malformations of the cortical spacing of the thalamocortical components, without concurrent malformations of the intracortical components of individual whisker functional representations. Overall, these results suggest that a developmental guidance label, such as Ephrin-A5, is involved in establishing certain spatial relationships of the functional organization of the adult neocortex, and they underscore the advantage of investigating gene manipulation using in vivo functional imaging.
Jürgen Löschinger - One of the best experts on this subject based on the ideXlab platform.
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On the turning of Xenopus retinal axons induced by Ephrin-A5
Development, 2003Co-Authors: Christine Weinl, Uwe Drescher, Susanne Lang, Friedrich Bonhoeffer, Jürgen LöschingerAbstract:The Eph family of receptor tyrosine kinases and their ligands, the Ephrins, play important roles during development of the nervous system. Frequently they exert their functions through a repellent mechanism, so that, for example, an axon expressing an Eph receptor does not invade a territory in which an Ephrin is expressed. Eph receptor activation requires membrane-associated ligands. This feature discriminates Ephrins from other molecules sculpturing the nervous system such as netrins, slits and class 3 semaphorins, which are secreted molecules. While the ability of secreted molecules to guide axons, i.e. to change their growth direction, is well established in vitro, little is known about this for the membrane-bound Ephrins. Here we set out to investigate – using Xenopus laevis retinal axons – the properties of substratum-bound and (artificially) soluble forms of Ephrin-A5 (Ephrin-A5-Fc) to guide axons. We find – as expected on the basis of chick experiments – that, when immobilised in the stripe assay, Ephrin-A5 has a repellent effect such that retinal axons avoid Ephrin-A5-Fc-containing lanes. Also, retinal axons react with repulsive turning or growth cone collapse when confronted with Ephrin-A5-Fc bound to beads. However, when added in soluble form to the medium, Ephrin-A5 induces growth cone collapse, comparable to data from chick. The analysis of growth cone behaviour in a gradient of soluble Ephrin-A5 in the `turning assay9 revealed a substratum-dependent reaction of Xenopus retinal axons. On fibronectin, we observed a repulsive response, with the turning of growth cones away from higher concentrations of Ephrin-A5. On laminin, retinal axons turned towards higher concentrations, indicating an attractive effect. In both cases the turning response occurred at a high background level of growth cone collapse. In sum, our data indicate that Ephrin-As are able to guide axons in immobilised bound form as well as in the form of soluble molecules. To what degree this type of guidance is relevant for the in vivo situation remains to be shown.
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On the turning of Xenopus retinal axons induced by Ephrin-A5
Development, 2003Co-Authors: Christine Weinl, Uwe Drescher, Susanne Lang, Friedrich Bonhoeffer, Jürgen LöschingerAbstract:The Eph family of receptor tyrosine kinases and their ligands, the Ephrins, play important roles during development of the nervous system. Frequently they exert their functions through a repellent mechanism, so that, for example, an axon expressing an Eph receptor does not invade a territory in which an Ephrin is expressed. Eph receptor activation requires membrane-associated ligands. This feature discriminates Ephrins from other molecules sculpturing the nervous system such as netrins, slits and class 3 semaphorins, which are secreted molecules. While the ability of secreted molecules to guide axons, i.e. to change their growth direction, is well established in vitro, little is known about this for the membrane-bound Ephrins. Here we set out to investigate – using Xenopus laevis retinal axons – the properties of substratum-bound and (artificially) soluble forms of Ephrin-A5 (Ephrin-A5-Fc) to guide axons. We find – as expected on the basis of chick experiments – that, when immobilised in the stripe assay, Ephrin-A5 has a repellent effect such that retinal axons avoid Ephrin-A5-Fc-containing lanes. Also, retinal axons react with repulsive turning or growth cone collapse when confronted with Ephrin-A5-Fc bound to beads. However, when added in soluble form to the medium, Ephrin-A5 induces growth cone collapse, comparable to data from chick. The analysis of growth cone behaviour in a gradient of soluble Ephrin-A5 in the `turning assay9 revealed a substratum-dependent reaction of Xenopus retinal axons. On fibronectin, we observed a repulsive response, with the turning of growth cones away from higher concentrations of Ephrin-A5. On laminin, retinal axons turned towards higher concentrations, indicating an attractive effect. In both cases the turning response occurred at a high background level of growth cone collapse. In sum, our data indicate that Ephrin-As are able to guide axons in immobilised bound form as well as in the form of soluble molecules. To what degree this type of guidance is relevant for the in vivo situation remains to be shown.