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

William Andrews, Anastasia Liapi, Céline Plachez, Laura Camurri, Jiangyang Zhang, Susumu Mori, Fujio Murakami, John G. Parnavelas, Vasi Sundaresan, Linda J. Richards

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2243-2252
Number of pages10
JournalDevelopment
Volume133
Issue number11
DOIs
StatePublished - Jun 2006

Keywords

  • Axon guidance
  • Cell migration
  • Corpus callosum
  • Hippocampal commissure
  • Mouse
  • Slit
  • Thalamocortical axons

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

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