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

Zimmer, Geraldine; Rudolph, Judith; Landmann, Julia; Gerstmann, Katrin; Steinecke, André; Gampe, Christin; Bolz, Jürgen

doi:10.1523/jneurosci.4690-11.2011

Cited by 66 publications

(85 citation statements)

References 66 publications

(99 reference statements)

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“…2B,C). A straightforward interpretation of these experiments is that EphA4 elicits reverse signaling that exerts a repulsive effect on cortical interneurons, as shown previously for EphA4 forward signaling with ephrin ligands, such as ephrin A5, A3 and B3 (Zimmer et al, 2008;Rudolph et al, 2011;Zimmer et al, 2011).…”

Section: Eph/ephrin Interactions In Mge-derived Neuronssupporting

confidence: 72%

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EphA/ephrin A reverse signaling promotes the migration of cortical interneurons from the medial ganglionic eminence

et al. 2014

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Inhibitory interneurons control the flow of information and synchronization in the cerebral cortex at the circuit level. During embryonic development, multiple subtypes of cortical interneurons are generated in different regions of the ventral telencephalon, such as the medial and caudal ganglionic eminence (MGE and CGE), as well as the preoptic area (POA). These neurons then migrate over long distances towards their cortical target areas. Diverse families of diffusible and cell-bound signaling molecules, including the Eph/ephrin system, regulate and orchestrate interneuron migration. Ephrin A3 and A5, for instance, are expressed at the borders of the pathway of MGE-derived interneurons and prevent these cells from entering inappropriate regions via EphA4 forward signaling. We found that MGE-derived interneurons, in addition to EphA4, also express ephrin A and B ligands, suggesting Eph/ephrin forward and reverse signaling in the same cell. In vitro and in vivo approaches showed that EphA4-induced reverse signaling in MGE-derived interneurons promotes their migration and that this effect is mediated by ephrin A2 ligands. In EphA4 mutant mice, as well as after ephrin A2 knockdown using in utero electroporation, we found delayed interneuron migration at embryonic stages. Thus, besides functions in guiding MGE-derived interneurons to the cortex through forward signaling, here we describe a novel role of the ephrins in driving these neurons to their target via reverse signaling.

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Section: Eph/ephrin Interactions In Mge-derived Neuronssupporting

confidence: 72%

“…In our previous work, we focused on the repercussions of complementary expression patterns of EphA4 and ephrin ligands in guiding MGE-derived interneurons through the basal telencephalon (Zimmer et al, 2008;Zimmer et al, 2011). As illustrated in Fig.…”

Section: Resultsmentioning

confidence: 99%

EphA/ephrin A reverse signaling promotes the migration of cortical interneurons from the medial ganglionic eminence

et al. 2014

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“…Since striatal interneurons also express ErbB4 receptors, additional mechanisms might exist to prevent striatal interneurons from populating the cortex. Eph receptor tyrosine kinase and their ephrin ligands are membrane-bound or transmembrane proteins that mediate cell repulsion in a large variety of biological contexts, and are known to be expressed in the developing telencephalon (Passante et al, 2008;Zimmer et al, 2011). For instance, the EphB receptors EphB1 and EphB3 are expressed both in the MGE and the striatum (Fig.…”

Section: Eph/ephrin Signaling Mediates the Cortical Repulsion Of Strimentioning

confidence: 99%

“…Multiple lines of evidence support the notion that the guidance of cortical interneurons involves the simultaneous activity of chemoattractive factors released by intermediate targets or by the cortex, and chemorepulsive molecules produced by territories that cortical interneurons must avoid, such as the striatum and the preoptic area Wichterle et al, 2003). Moreover, many of the attractive and repulsive molecules involved in the guidance of cortical interneurons have been identified Powell et al, 2001;Flames et al, 2004;Pozas and Ibañez, 2005;Zimmer et al, 2008;Hernández-Miranda et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Molecular Mechanisms Controlling the Migration of Striatal Interneurons

Villar-Cerviño

Kappeler

Nóbrega-Pereira

et al. 2015

Journal of Neuroscience

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In the developing telencephalon, the medial ganglionic eminence (MGE) generates many cortical and virtually all striatal interneurons. While the molecular mechanisms controlling the migration of interneurons to the cortex have been extensively studied, very little is known about the nature of the signals that guide interneurons to the striatum. Here we report that the allocation of MGE-derived interneurons in the developing striatum of the mouse relies on a combination of chemoattractive and chemorepulsive activities. Specifically, interneurons migrate toward the striatum in response to Nrg1/ErbB4 chemoattraction, and avoid migrating into the adjacent cortical territories by a repulsive activity mediated by EphB/ephrinB signaling. Our results also suggest that the responsiveness of MGE-derived striatal interneurons to these cues is at least in part controlled by the postmitotic activity of the transcription factor Nkx2-1. This study therefore reveals parallel mechanisms for the migration of MGE-derived interneurons to the striatum and the cerebral cortex.

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“…Expression constructs for Neurog2, Ascl1, or Dlx2 were transfected into P19 cells and total RNA was extracted two days after transfection. By using quantitative RT-PCR (qRT-PCR), we examined the expression level of Ephs and Efns that have been detected in the developing telencephalon 29 . Because Neurog2 promotes differentiation of glutamatergic neurons 17 , genes induced by both Neurog2 and Ascl1 were excluded.…”

Section: Ephb2 Acts Downstream Of Ascl1 In Regulating Tangential Migrmentioning

confidence: 99%

Ascl1 promotes tangential migration and confines migratory routes by induction of Ephb2 in the telencephalon

Liu¹,

Tsai

Chen

et al. 2017

Mechanisms of Development

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During development, cortical interneurons generated from the ventral telencephalon migrate tangentially into the dorsal telencephalon. Although Achaete-scute family bHLH transcription factor 1 (Ascl1) plays important roles in the developing telencephalon, whether Ascl1 regulates tangential migration remains unclear. Here, we found that Ascl1 promoted tangential migration along the ventricular zone/subventricular zone (VZ/SVZ) and intermediate zone (IZ) of the dorsal telencephalon. Distal-less homeobox 2 (Dlx2) acted downstream of Ascl1 in promoting tangential migration along the VZ/SVZ but not IZ. We further identified Eph receptor B2 (Ephb2) as a direct target of Ascl1. Knockdown of EphB2 disrupted the separation of the VZ/SVZ and IZ migratory routes. Ephrin-A5, a ligand of EphB2, was sufficient to repel both Ascl1-expressing cells in vitro and tangentially migrating cortical interneurons in vivo. Together, our results demonstrate that Ascl1 induces expression of Dlx2 and Ephb2 to maintain distinct tangential migratory routes in the dorsal telencephalon.The cerebral cortex is important for executing high-order brain functions, such as sensory perception, motor control and cognition. Proper functions of the cerebral cortex require coordination between excitatory (glutamatergic) projection neurons and inhibitory (GABAergic) interneurons. Many neurological and psychological disorders, such as epilepsy, autism, schizophrenia, and Alzheimer's disease, may be resulted from an imbalance of excitatory and inhibitory neuronal activities or the dysfunction of interneurons 1,2 . Interestingly, glutamatergic neurons and GABAergic interneurons are produced from different regions of the developing brain. Glutamatergic neurons are generated from neural progenitors in the dorsal telencephalon, which develops into the cerebral cortex. GABAergic cortical interneurons are remotely derived from neural progenitors in the ventral telencephalon, which develops into the striatum and globus pallidus 3 . Around 85% of cortical interneurons are generated from the medial ganglionic eminence (MGE) and the rest are generated from the caudal ganglionic eminence (CGE) 4,5 . Once generated in the ventricular zone (VZ), glutamatergic neurons and GABAergic interneurons migrate toward final destinations through distinct paths. Glutamatergic neurons undergo radial migration to reach the cortical plate (CP) 6 . Interneurons take a long tangentially migratory path from the ventral telencephalon toward the striatum or the cerebral cortex 3 . When cortical interneurons reach the dorsal telencephalon, they continue migrating tangentially through three migratory routes: the marginal zone (MZ), intermediate zone (IZ) or ventricular/subventricular zone (VZ/SVZ) of the dorsal telencephalon 7,8 . Upon arrival at destined region, interneurons switch to migrate radially until they reach specific layers of the cerebral cortex, where they integrate into local neuronal circuits. Since cortical interneurons go through such a complicated migratory path, it is impo...

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

Cited by 66 publications

References 66 publications

EphA/ephrin A reverse signaling promotes the migration of cortical interneurons from the medial ganglionic eminence

EphA/ephrin A reverse signaling promotes the migration of cortical interneurons from the medial ganglionic eminence

Molecular Mechanisms Controlling the Migration of Striatal Interneurons

Ascl1 promotes tangential migration and confines migratory routes by induction of Ephb2 in the telencephalon

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