Miswiring of Limbic Thalamocortical Projections in the Absence of Ephrin-A5

Uziel, Daniela; Mühlfriedel, Sven; Zarbalis, Konstantinos; Wurst, Wolfgang; Levitt, Pat; Bolz, Jürgen

doi:10.1523/jneurosci.22-21-09352.2002

Cited by 60 publications

(42 citation statements)

References 37 publications

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“…To pursue genetic knockdown of ephrin-A5 signaling, we used siRNA against ephrin-A5. This is because transgenic mice with KOs in ephrinAs or EphAs have an abnormal cortical organization, including abnormal cortical afferents, disturbed intracortical connections, and altered visual and somatosensory maps (18)(19)(20)(21), making the analysis of rewiring in the adult brain after stroke compromised by profound developmental miswiring in cortex. Ephrin-A5 expression is knocked down by local delivery of ephrin-A5 siRNA (Fig.…”

Section: Resultsmentioning

confidence: 99%

A role for ephrin-A5 in axonal sprouting, recovery, and activity-dependent plasticity after stroke

Overman¹,

Clarkson

Wanner³

et al. 2012

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

227

310

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Stroke causes loss of neurological function. Recovery after stroke is facilitated by forced use of the affected limb and is associated with sprouting of new connections, a process that is sharply confined in the adult brain. We show that ephrin-A5 is induced in reactive astrocytes in periinfarct cortex and is an inhibitor of axonal sprouting and motor recovery in stroke. Blockade of ephrin-A5 signaling using a unique tissue delivery system induces the formation of a new pattern of axonal projections in motor, premotor, and prefrontal circuits and mediates recovery after stroke in the mouse through these new projections. Combined blockade of ephrin-A5 and forced use of the affected limb promote new and surprisingly widespread axonal projections within the entire cortical hemisphere ipsilateral to the stroke. These data indicate that stroke activates a newly described membrane-bound astrocyte growth inhibitor to limit neuroplasticity, activity-dependent axonal sprouting, and recovery in the adult.cortical map | regeneration | repair | motor function | EphA4

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Section: Resultsmentioning

confidence: 99%

A role for ephrin-A5 in axonal sprouting, recovery, and activity-dependent plasticity after stroke

Overman¹,

Clarkson

Wanner³

et al. 2012

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

227

310

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“…Due to the redundancy and high promiscuity of interactions of the Eph/ephrin system, the deletion of an individual gene of the Eph/ephrin system mostly leads to only subtle albeit highly reproducible abnormalities (Uziel et al, 2002(Uziel et al, , 2008Guellmar et al, 2009;Zimmer et al, 2010b) or even to no detectable phenotypes (Feldheim et al, 2000;Mendes et al, 2006). In addition, the complete knockdown of a single gene can lead to adaptive or compensatory changes in other genes.…”

Section: Disorganized Migratory Interneurons In the Poa And Mge Of Mumentioning

confidence: 99%

Bidirectional EphrinB3/EphA4 Signaling Mediates the Segregation of Medial Ganglionic Eminence- and Preoptic Area-Derived Interneurons in the Deep and Superficial Migratory Stream

Zimmer¹,

Rudolph²,

Landmann³

et al. 2011

J. Neurosci.

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The integration of interneuron subtypes into specific microcircuits is essential for proper cortical function. Understanding to what extent interneuron diversity is regulated and maintained during development might help to reveal the principles that govern their role as synchronizing elements as well as causes for dysfunction. Particular interneuron subtypes are generated in a temporally regulated manner in the medial ganglionic eminence (MGE), the caudal ganglionic eminence, and the preoptic area (POA) of the basal telencephalon. Long-range tangential migration from their site of origin to cortical targets is orchestrated by a variety of attractive, repulsive, membrane-bound, and secreted signaling molecules, to establish the critical balance of inhibition and excitation. It remains unknown whether interneurons deriving from distinct domains are predetermined to migrate in particular routes and whether this process underlies cell type-specific regulation. We found that POA-and MGE-derived cortical interneurons migrate within spatially segregated corridors. EphrinB3, expressed in POA-derived interneurons traversing the superficial route, acts as a repellent signal for deeply migrating interneurons born in the MGE, which is mediated by EphA4 forward signaling. In contrast, EphA4 induces repulsive ephrinB3 reverse signaling in interneurons generated in the POA, restricting this population to the superficial path. Perturbation of this bidirectional ephrinB3/EphA4 signaling in vitro and in vivo leads to a partial intermingling of cells in these segregated migratory pathways. Thus, we conclude that cell contact-mediated bidirectional ephrinB3/EphA4 signaling mediates the sorting of MGE-and POA-derived interneurons in the deep and superficial migratory stream.

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“…Placing crystals of DiI into S1 of ephrin-A5 knockout and wild-type animals, we described a miswired projection from dorsomedial thalamic nuclei to S1 at P8. These results suggest that in the absence of ephrin-A5, thalamic fibers that normally innervate limbic regions reroute and invade neighboring neocortical areas (Uziel et al, 2002). Dufour et al (2003) looked for miswiring of thalamic axons in older (P14 to P18) ephrin-A5 knockout animals, but had negative results.…”

Section: Ephrins Direct Thalamic Axons To Find Their Cortical Targetmentioning

confidence: 98%

“…Recent data from Niehage et al (2005) point to the expression of some ephrins and Eph receptors in the hypothalamus, which may also contribute as repulsive cues to avoid thalamic fibers to extend ventrally. Moreover, the expression of ephrins in the cortex and Eph receptors by thalamic cells seems to play an important role for thalamic axons to choose their correct cortical target area Mackarehtschian et al, 1999;Vanderhaeghen et al, 2000;Uziel et al, 2002); this will be discussed later in this review.…”

Section: A Small Step For An Axon a Giant Leap For Brain Circuitrymentioning

confidence: 99%

“…In the developing central nervous system, ephrin ligands and their receptors are extensively expressed and contribute to the formation of connections between brain regions (see, for example, Tuzi and Gullick, 1994;Drescher et al, 1995;Gao et al, 1998;Mackarehtschian et al, 1999;Vanderhaeghen et al, 2000;Uziel et al, 2002;Dufour et al, 2003). In order to identify candidate molecules of the Eph/ephrin family, which might contribute to the development of the thalamocortical system, we performed a comprehensive in situ hybridization screening survey for transcripts of all known members of the family at critical developmental stages of the somatosensory and frontal cortical pathways (Niehage et al, 2005).…”

Section: Who Is Who In the Eph/ephrin Familymentioning

confidence: 99%

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Connecting thalamus and cortex: The role of ephrins

et al. 2006

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The complex task of wiring up the brain during embryonic development is achieved by a multitude of guidance signals acting in complex combinations to drive growing axons to their proper targets. The somatosensory system provides an extensively studied model system featuring many universal mechanisms of neural development. In rodents, it constitutes an important model to study how precise topographic connections are achieved. Recent evidence suggests that the Eph/ephrin family of guidance molecules is of pivotal importance for the development of the somatosensory system. Members of Eph/ephrin family are thought to be involved in the global presorting of thalamic axons projecting to the cortex, in labeling specific cortical areas for innervation, in providing topographic cues within the target area, and in distinguishing cortical layers for intracortical wiring. The Eph/ephrin system also seems to contribute to the formation of specific corticothalamic feedback projections. So far, the functions of only a few members of the Eph/ephrin family have been examined, but expression analysis indicates complex combinatorial effects of these signaling molecules. Understanding the Eph/ephrin wiring code is expected to yield new insights into the development and plasticity of brain circuits involved in higher functions.

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Miswiring of Limbic Thalamocortical Projections in the Absence of Ephrin-A5

Cited by 60 publications

References 37 publications

A role for ephrin-A5 in axonal sprouting, recovery, and activity-dependent plasticity after stroke

A role for ephrin-A5 in axonal sprouting, recovery, and activity-dependent plasticity after stroke

Bidirectional EphrinB3/EphA4 Signaling Mediates the Segregation of Medial Ganglionic Eminence- and Preoptic Area-Derived Interneurons in the Deep and Superficial Migratory Stream

Connecting thalamus and cortex: The role of ephrins

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