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First published online May 11, 2006
doi: 10.1242/10.1242/dev.02379

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Robo1 regulates the development of major axon tracts and interneuron migration in the forebrain

William Andrews^1,2,*, Anastasia Liapi^1,*, Céline Plachez^3,*, Laura Camurri², Jiangyang Zhang⁴, Susumu Mori^4,5, Fujio Murakami⁶, John G. Parnavelas¹, Vasi Sundaresan^7, and Linda J. Richards^3,8,

¹ Department of Anatomy and Developmental Biology, University College London, London WC1E 6BT, UK.
² MRC Centre for Developmental Neurobiology, King's College London, London SE1 1UL, UK.
³ The University of Maryland School of Medicine, Department of Anatomy and Neurobiology, and The Program in Neuroscience, Baltimore, MD 21201, USA.
⁴ Johns Hopkins University School of Medicine, Department of Radiology, Division of NMR Research and Department of Biomedical Engineering, Baltimore, MD 21205, USA.
⁵ F. M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD 21205, USA.
⁶ Osaka University, Osaka, Japan.
⁷ Department of Cellular Pathology, St Margarets Hospital, The Plain, Epping CM16 6TN, UK.
⁸ The University of Queensland, School of Biomedical Sciences and The Queensland Brain Institute, Brisbane, Queensland, Australia.

Authors for correspondence (e-mail richards{at}uq.edu.au and vasi.sundaresan{at}kcl.ac.uk)

Accepted 23 March 2006

The Slit genes encode secreted ligands that regulate axon branching, commissural axon pathfinding and neuronal migration. The principal identified receptor for Slit is Robo (Roundabout in Drosophila). To investigate Slit signalling in forebrain development, we generated Robo1 knockout mice by targeted deletion of exon 5 of the Robo1 gene. Homozygote knockout mice died at birth, but prenatally displayed major defects in axon pathfinding and cortical interneuron migration. Axon pathfinding defects included dysgenesis of the corpus callosum and hippocampal commissure, and abnormalities in corticothalamic and thalamocortical targeting. Slit2 and Slit1/2 double mutants display malformations in callosal development, and in corticothalamic and thalamocortical targeting, as well as optic tract defects. In these animals, corticothalamic axons form large fasciculated bundles that aberrantly cross the midline at the level of the hippocampal and anterior commissures, and more caudally at the medial preoptic area. Such phenotypes of corticothalamic targeting were not observed in Robo1 knockout mice but, instead, both corticothalamic and thalamocortical axons aberrantly arrived at their respective targets at least 1 day earlier than controls. By contrast, in Slit mutants, fewer thalamic axons actually arrive in the cortex during development. Finally, significantly more interneurons (up to twice as many at E12.5 and E15.5) migrated into the cortex of Robo1 knockout mice, particularly in both rostral and parietal regions, but not caudal cortex. These results indicate that Robo1 mutants have distinct phenotypes, some of which are different from those described in Slit mutants, suggesting that additional ligands, receptors or receptor partners are likely to be involved in Slit/Robo signalling.

Key words: Thalamocortical axons, Corpus callosum, Hippocampal commissure, Axon guidance, Cell migration, Slit, Mouse