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      Draxin from neocortical neurons controls the guidance of thalamocortical projections into the neocortex

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          Abstract

          The thalamocortical tract carries sensory information to the neocortex. It has long been recognized that the neocortical pioneer axons of subplate neurons are essential for thalamocortical development. Herein we report that an axon guidance cue, draxin, is expressed in early-born neocortical neurons, including subplate neurons, and is necessary for thalamocortical development. In draxin −/− mice, thalamocortical axons do not enter the neocortex. This phenotype is sufficiently rescued by the transgenic expression of draxin in neocortical neurons. Genetic interaction data suggest that draxin acts through Deleted in colorectal cancer (DCC) and Neogenin (Neo1), to regulate thalamocortical projections in vivo. Draxin promotes the outgrowth of thalamic axons in vitro and this effect is abolished in thalamic neurons from Dcc and Neo1 double mutants. These results suggest that draxin from neocortical neurons controls thalamocortical projections into the neocortex, and that this effect is mediated through the DCC and Neo1 receptors.

          Abstract

          During neural development thalamocortical axons follow corticofugal projections into the neocortex. Here, using a combination of knock down and rescue experiments, the authors show that Draxin expression in neocortical cells promotes thalamic axon projections from the internal capsule.

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          Most cited references64

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          Neuronal subtype specification in the cerebral cortex.

          In recent years, tremendous progress has been made in understanding the mechanisms underlying the specification of projection neurons within the mammalian neocortex. New experimental approaches have made it possible to identify progenitors and study the lineage relationships of different neocortical projection neurons. An expanding set of genes with layer and neuronal subtype specificity have been identified within the neocortex, and their function during projection neuron development is starting to be elucidated. Here, we assess recent data regarding the nature of neocortical progenitors, review the roles of individual genes in projection neuron specification and discuss the implications for progenitor plasticity.
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            Tbr1 regulates differentiation of the preplate and layer 6.

            During corticogenesis, early-born neurons of the preplate and layer 6 are important for guiding subsequent neuronal migrations and axonal projections. Tbr1 is a putative transcription factor that is highly expressed in glutamatergic early-born cortical neurons. In Tbr1-deficient mice, these early-born neurons had molecular and functional defects. Cajal-Retzius cells expressed decreased levels of Reelin, resulting in a reeler-like cortical migration disorder. Impaired subplate differentiation was associated with ectopic projection of thalamocortical fibers into the basal telencephalon. Layer 6 defects contributed to errors in the thalamocortical, corticothalamic, and callosal projections. These results show that Tbr1 is a common genetic determinant for the differentiation of early-born glutamatergic neocortical neurons and provide insights into the functions of these neurons as regulators of cortical development.
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              Phenotype of mice lacking functional Deleted in colorectal cancer (Dcc) gene.

              The DCC (Deleted in colorectal cancer) gene was first identified as a candidate for a tumour-suppressor gene on human chromosome 18q. More recently, in vitro studies in rodents have provided evidence that DCC might function as a receptor for the axonal chemoattractant netrin-1. Inactivation of the murine Dcc gene caused defects in axonal projections that are similar to those observed in netrin-1-deficient mice but did not affect growth, differentiation, morphogenesis or tumorigenesis in mouse intestine. These observations fail to support a tumour-suppressor function for Dcc, but are consistent with the hypothesis that DCC is a component of a receptor for netrin-1.
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                Author and article information

                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group
                2041-1723
                14 December 2015
                2015
                : 6
                : 10232
                Affiliations
                [1 ]Faculty of Life Sciences, Department of Developmental Neurobiology, Kumamoto University , Kumamoto 860-8556, Japan
                [2 ]Department of Biophysical Genetics, Graduate School of Medical Sciences, Kanazawa University , Takara-machi 13-1, Ishikawa 920–8640, Japan
                [3 ]Division of Neurobiology and Anatomy, Graduate School of Medical and Dental Sciences, Niigata University , Niigata 951–8510, Japan
                [4 ]Brain/Liver Interface Medicine Research Center, Kanazawa University , Ishikawa 920-8640, Japan
                Author notes
                [*]

                These authors contributed equally to this work.

                [†]

                Deceased.

                Article
                ncomms10232
                10.1038/ncomms10232
                4682175
                26659141
                8dd36e28-d472-4b45-9432-699ebeaa4cbf
                Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 15 September 2015
                : 19 November 2015
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