p75NTR Mediates Ephrin-A Reverse Signaling Required for Axon Repulsion and Mapping

Molecular Neurobiology Laboratory, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Neuron (Impact Factor: 15.98). 10/2008; 59(5):746-58. DOI: 10.1016/j.neuron.2008.07.032
Source: PubMed

ABSTRACT Reverse signaling by ephrin-As upon binding EphAs controls axon guidance and mapping. Ephrin-As are GPI-anchored to the membrane, requiring that they complex with transmembrane proteins that transduce their signals. We show that the p75 neurotrophin receptor (NTR) serves this role in retinal axons. p75(NTR) and ephrin-A colocalize within caveolae along retinal axons and form a complex required for Fyn phosphorylation upon binding EphAs, activating a signaling pathway leading to cytoskeletal changes. In vitro, retinal axon repulsion to EphAs by ephrin-A reverse signaling requires p75(NTR), but repulsion to ephrin-As by EphA forward signaling does not. Constitutive and retina-specific p75(NTR) knockout mice have aberrant anterior shifts in retinal axon terminations in superior colliculus, consistent with diminished repellent activity mediated by graded ephrin-A reverse signaling induced by graded collicular EphAs. We conclude that p75(NTR) is a signaling partner for ephrin-As and the ephrin-A- p75(NTR) complex reverse signals to mediate axon repulsion required for guidance and mapping.

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    • "According to this model, a second gradient system—formed by ephrinAs with a receptor function expressed on retinal axons (nasal > temporal) and EphAs with a ligand function expressed in the SC (rostral > caudal)—also contributes to the mapping process (Figure 1; Suetterlin et al., 2012). This model is supported by a number of EphA KO and knock-in approaches (Carreres et al., 2011; Lim et al., 2008; Rashid et al., 2005; Yoo et al., 2011) as well as in vitro experiments (Gebhardt et al., 2012; Lim et al., 2008; Marler et al., 2010; Rashid et al., 2005). "
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    ABSTRACT: EphrinAs and EphAs play critical roles during topographic map formation in the retinocollicular projection; however, their complex expression patterns in both the retina and superior colliculus (SC) have made it difficult to uncover their precise mechanisms of action. We demonstrate here that growth cones of temporal axons collapse when contacting nasal axons in vitro, and removing ephrinAs from axonal membranes by PI-PLC treatment abolishes this response. In conditional knockout mice, temporal axons display no major targeting defects when ephrinA5 is removed only from the SC, but substantial mapping defects were observed when ephrinA5 expression was removed from both the SC and from the retina, with temporal axons invading the target areas of nasal axons. Together, these data indicate that ephrinA5 drives repellent interactions between temporal and nasal axons within the SC, and demonstrates for the first time that target-independent mechanisms play an essential role in retinocollicular map formation in vivo.
    Neuron 10/2014; 84(4). DOI:10.1016/j.neuron.2014.09.023 · 15.98 Impact Factor
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    • "These results suggest that the EphA7 barriers may provide a repulsive force that constrains the axonal navigation pathway and prevents axons for exiting to the outgrowth corridor. Similar repulsive forces mediated by EphA7 have been described in wild type retinal axons (Rashid et al., 2005; Lim et al., 2008). At the lateral RP, axons are in contact with SCO-spondin. "
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    ABSTRACT: Bilaterally symmetric organisms need to exchange information between the two sides of their bodies in order to integrate sensory inputs and coordinate motor control. This exchange occurs through commissures formed by neurons that project axons across the midline to the contralateral side of the central nervous system. The posterior commissure is the first transversal axonal tract of the embryonic vertebrate brain. It is located in the dorsal portion of the prosomere 1, at the caudal diencephalon. The axons of the posterior commissure principally come from neurons of ventrolateral and dorsolateral pretectal nuclei (parvocellular and magnocellular nucleus of the posterior commissure, respectively) that extend their axons toward the dorsal region. The trajectory of these axons can be divided into the following three stages: (1) dorsal axon extension towards the lateral roof plate; (2) fasciculation in the lateral roof plate; and (3) midline decision of turning to the ipsilateral side or continuing to the opposite side. The mechanisms and molecules that guide the axons during these steps are unknown. In the present work, immunohistochemical and in situ hybridization analyses were performed, with results suggesting the participation of EphA7 in guiding axons from the ventral to the dorsal region of the prosomere 1 through the generation of an axonal corridor limited by repulsive EphA7 walls. At the lateral roof plate, the axons became fasciculated in presence of SCO-spondin until reaching the midline. Finally, EphA7 expression was observed in the diencephalic midline roof plate, specifically in the region where some axons turn to the ipsilateral side, suggesting its participation in this decision. In summary, the present work proposes a mechanism of posterior commissure formation orchestrated by the complementary expression of the axon guidance cues SCO-spondin and EphA7.
    Frontiers in Neuroanatomy 06/2014; 8:49. DOI:10.3389/fnana.2014.00049 · 4.18 Impact Factor
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    • "For instance, the neurotrophin BDNF promotes interstitial branching in vitro through a mechanism dependent on TrkB (Marler et al., 2008). EphrinAs on RGC axons also interact with another BDNF receptor, p75 (Lim et al., 2008). The precise function of p75 is unclear, but it is likely that its activation does not reduce branching per se but rather inhibits BDNF/ TrkB signaling. "
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    ABSTRACT: The visual system is beautifully crafted to transmit information of the external world to visual processing and cognitive centers in the brain. For visual information to be relayed to the brain, a series of axon pathfinding events must take place to ensure that the axons of retinal ganglion cells, the only neuronal cell type in the retina that sends axons out of the retina, find their way out of the eye to connect with targets in the brain. In the past few decades, the power of molecular and genetic tools, including the generation of genetically manipulated mouse lines, have multiplied our knowledge about the molecular mechanisms involved in the sculpting of the visual system. Here, we review major advances in our understanding of the mechanisms controlling the differentiation of RGCs, guidance of their axons from the retina to the primary visual centers, and the refinement processes essential for the establishment of topographic maps and eye-specific axon segregation. Human disorders, such as albinism and achiasmia, that impair RGC axon growth and guidance and, thus, the establishment of a fully functioning visual system will also be discussed. The eyes together with their connecting pathways to the brain form the visual system. In the eye, the cornea bends light rays and is primarily responsible for focusing the image on the retina. The lens behind the cornea inverts the image top to bottom and right to left. The retina, the receptive surface inside the back of the eye, is the struc-ture that translates light into nerve signals, and enables us to see under conditions that range from dark to sunlight, discriminate colors, and provide a high degree of visual precision. The retina consists of three layers of nerve cell bodies separated by two layers containing synapses made by the axons and dendrites of these cells. The back of the retina comprises the photoreceptors, the rods, and cones. The medial retinal layer contains three types of nerve cells, bipolar, horizontal, and amacrine cells. Bipolar cells receive input from the photoreceptors, and many of them feed directly into the retinal ganglion cells (RGCs). Horizontal cells connect receptors and bipolar cells by relatively long connections that run parallel to the retinal layers. Amacrine cells link bipolar cells and RGCs, the cells located in the inner retina. RGC axons pass across the surface of the retina and are collected in a bundle at the optic disk to leave the eye and form the optic nerve. There are approximately 20 RGC types that can be classified by morphological, molecular, and func-tional criteria. Each RGC type participates in distinct retinal circuits and projects to a specific set of targets in the brain (Coombs et al., 2007; Schmidt et al., 2011), including the main image-forming nuclei such as the lat-eral geniculate nucleus (LGN), the visual part of the thal-amus, and the superior colliculus (SC), located in the roof of the midbrain, that coordinates rapid movement of the eye (Figure 1). The optic axons from both eyes meet at the optic chiasm, which is located at the base of the hypothalamus. There, RGC axons from the nasal retina cross over to the opposite side of the brain (contralateral or commissural axons) while axons from the temporal retina turn to
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