Segregation and Pathfinding of Callosal Axons through EphA3 Signaling

Nishikimi, Mitsuaki; Oishi, Koji; Tabata, Hidenori; Torii, K.; Nakajima, Kazunori

doi:10.1523/jneurosci.3303-11.2011

Cited by 40 publications

(35 citation statements)

References 46 publications

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“…Previous studies using fluorescent carbocyanine dye (DiI) labeling of two distant cortical regions in separate mice already have suggested that axons from medial and lateral regions occupy dorsal and ventral positions within the CC, respectively (20,40). By dual labeling of cortical neurons in two defined cortical regions with the in utero electroporation method and quantitative image analysis of axon distribution at a high resolution over large areas, we now demonstrate that the topography of cortical neurons is tightly constrained by the D-V position of their axons within the CC.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Axon position within the corpus callosum determines contralateral cortical projection

Zhou

Wen

She

et al. 2013

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

116

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How developing axons in the corpus callosum (CC) achieve their homotopic projection to the contralateral cortex remains unclear. We found that axonal position within the CC plays a critical role in this projection. Labeling of nearby callosal axons in mice showed that callosal axons were segregated in an orderly fashion, with those from more medial cerebral cortex located more dorsally and subsequently projecting to more medial contralateral cortical regions. The normal axonal order within the CC was grossly disturbed when semaphorin3A/neuropilin-1 signaling was disrupted. However, the order in which axons were positioned within the CC still determined their contralateral projection, causing a severe disruption of the homotopic contralateral projection that persisted at postnatal day 30, when the normal developmental refinement of contralateral projections is completed in wild-type (WT) mice. Thus, the orderly positioning of axons within the CC is a primary determinant of how homotopic interhemispheric projections form in the contralateral cortex.axon development | axon fiber order | cortical axon guidance | cortical development T he largest commissural tract in the human brain is the corpus callosum (CC), with more than 200 million axons connecting the two cerebral hemispheres. Callosal axons originate primarily from neurons of layer II/III and layer V of the neocortex (1) and project homotopically to the contralateral cortex. For example, callosal axons of the primary motor cortex (M1) and primary somatosensory cortex (S1) project to topographically equivalent locations in the contralateral M1 and S1, respectively. This pattern of homotopic projection is essential for coordinated motor and somatosensory functions as well as for higher associative and cognitive processes (2-4). Abnormal CC development has been noted in psychiatric and developmental disorders (5, 6), and deviant asymmetry of cortical areas found in patients with developmental dyslexia also may be attributed to callosal abnormalities (7,8). However, the mechanism by which normal homotopic projection pattern is achieved during development remains largely unknown.The majority of axonal projections in the nervous system are organized topographically. To facilitate the formation of orderly projections over long distances, axons originating from adjacent areas may preserve their topographic order within the nerve tract along their entire path toward the target region (9, 10). This preservation of topographic order has been shown in the thalamocortical tract (11)(12)(13)(14) and in the optic and olfactory nerves (15-17). By performing a series of random microinjections of biotinylated dextran amine in the dorsal thalamus and reconstructing the labeled fibers, Powell et al. (14) showed that labeled axons within the thalamocortical tract preserve a topography similar to that in the ventral telencephalon before they reach the cortex. In the developing olfactory system, axons within the olfactory nerve from three different regions of the olfactory epitheli...

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Section: Discussionmentioning

confidence: 99%

“…The contribution from Sema3C secreted by cells within the CC also has been shown to guide the bundling of CC axons (20). In addition, ephrin receptor A also is expressed in the ventral CC axons (20,40), suggesting that ephrin/Eph signaling also may play a role in maintaining the axon order within the CC.…”

Section: M1mentioning

confidence: 99%

Axon position within the corpus callosum determines contralateral cortical projection

Zhou

Wen

She

et al. 2013

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

116

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“…In addition, we recently demonstrated that cingulate callosal axons also express the axon guidance receptor DCC, and that these axons are attracted towards its ligand, NTN1, at the midline (Fothergill et al, 2014). Similarly, other short-and longrange axon guidance molecules have been demonstrated to function in regulating neocortical callosal pathfinding (Shu and Richards, 2001;Shu et al, 2003;Andrews et al, 2006;Islam et al, 2009;Nishikimi et al, 2011). As callosal axons from the dorso-lateral cortex, where Nrp1 expression is absent, are able to project their axons medially (Zhou et al, 2013), it appears likely that other axon guidance mechanisms can guide callosal pathfinding in the absence of Nrp1 expression.…”

Section: Emx1 Mediates Cingulate Callosal Axon Guidance By Regulatingmentioning

confidence: 97%

EMX1 regulates NRP1-mediated wiring of the mouse anterior cingulate cortex

et al. 2015

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Transcription factors act during cortical development as master regulatory genes that specify cortical arealization and cellular identities. Although numerous transcription factors have been identified as being crucial for cortical development, little is known about their downstream targets and how they mediate the emergence of specific neuronal connections via selective axon guidance. The EMX transcription factors are essential for early patterning of the cerebral cortex, but whether EMX1 mediates interhemispheric connectivity by controlling corpus callosum formation remains unclear. Here, we demonstrate that in mice on the C57Bl/6 background EMX1 plays an essential role in the midline crossing of an axonal subpopulation of the corpus callosum derived from the anterior cingulate cortex. In the absence of EMX1, cingulate axons display reduced expression of the axon guidance receptor NRP1 and form aberrant axonal bundles within the rostral corpus callosum. EMX1 also functions as a transcriptional activator of Nrp1 expression in vitro, and overexpression of this protein in Emx1 knockout mice rescues the midline-crossing phenotype. These findings reveal a novel role for the EMX1 transcription factor in establishing cortical connectivity by regulating the interhemispheric wiring of a subpopulation of neurons within the mouse anterior cingulate cortex.

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“…In the past decades, detailed anatomical and physiological studies in animal models have improved our understanding of the organization and development of callosal connections [1–8]. Recent genetic studies have revealed molecular signals critical for the identity specification of callosal projection neurons [9–12] and axon guidance during the midline crossing [13–27]. These findings have been relevant for not only basic neuroscientists but also clinical neuroscientists, because malformations such as partial or complete agenesis of the corpus callosum are associated with many human congenital disorders [18, 22].…”

Section: Introductionmentioning

confidence: 99%

Activity-Dependent Callosal Axon Projections in Neonatal Mouse Cerebral Cortex

Tagawa

Hirano

2012

Neural Plasticity

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Callosal axon projections are among the major long-range axonal projections in the mammalian brain. They are formed during the prenatal and early postnatal periods in the mouse, and their development relies on both activity-independent and -dependent mechanisms. In this paper, we review recent findings about the roles of neuronal activity in callosal axon projections. In addition to the well-documented role of sensory-driven neuronal activity, recent studies using in utero electroporation demonstrated an essential role of spontaneous neuronal activity generated in neonatal cortical circuits. Both presynaptic and postsynaptic neuronal activities are critically involved in the axon development. Studies have begun to reveal intracellular signaling pathway which works downstream of neuronal activity. We also review several distinct patterns of neuronal activity observed in the developing cerebral cortex, which might play roles in activity-dependent circuit construction. Such neuronal activity during the neonatal period can be disrupted by genetic factors, such as mutations in ion channels. It has been speculated that abnormal activity caused by such factors may affect activity-dependent circuit construction, leading to some developmental disorders. We discuss a possibility that genetic mutation in ion channels may impair callosal axon projections through an activity-dependent mechanism.

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Segregation and Pathfinding of Callosal Axons through EphA3 Signaling

Cited by 40 publications

References 46 publications

Axon position within the corpus callosum determines contralateral cortical projection

Axon position within the corpus callosum determines contralateral cortical projection

EMX1 regulates NRP1-mediated wiring of the mouse anterior cingulate cortex

Activity-Dependent Callosal Axon Projections in Neonatal Mouse Cerebral Cortex

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