Cortical and thalamic axon pathfinding defects in Tbr1, Gbx2, and Pax6 mutant mice: evidence that cortical and thalamic axons interact and guide each other

J Comp Neurol. 2002 May 20;447(1):8-17. doi: 10.1002/cne.10219.


During development, cortical areas establish precise reciprocal projections with corresponding thalamic nuclei. Pioneer axons from the cortex and thalamus first meet in the intermediate zone of the subcortical telencephalon (subpallium). Their close interactions in the subpallium suggest that they may use each other for guidance. To test this hypothesis, the development of corticothalamic and thalamocortical connections was studied in mice with mutations of transcription factor genes expressed specifically in the cortex (Tbr1), the dorsal thalamus (Gbx2), or both (Pax6). In Tbr1 mutants, cortical pioneer axons entered the subpallium at the appropriate time, but most stopped growing without entering the diencephalon. Surprisingly, thalamic axons (which do not express Tbr1) deviated into the external capsule and amygdala regions, without entering the cortex. Conversely, in most Gbx2 mutants, thalamic axons were reduced in number and grew no farther than the subpallium. Cortical axons (which do not express Gbx2) grew into the subpallium but did not enter the diencephalon. In one Gbx2- /- case, sparse thalamocortical and corticothalamic projections both developed, but in no case did one projection reach its target and not the other. In Pax6 mutants, neither corticothalamic nor thalamocortical axons reached their targets. These results suggest that thalamocortical and corticothalamic projections may not form independently. After reaching the subpallium, each projection may require a molecularly intact reciprocal projection for further guidance. This type of mechanism ensures that thalamocortical and corticothalamic axons project reciprocally. However, the exact nature of the interaction between cortical and thalamic pioneer axons remains to be elucidated.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Animals, Newborn
  • Carbocyanines
  • Cell Communication / genetics
  • Cell Differentiation / genetics
  • Cerebral Cortex / embryology*
  • Cerebral Cortex / growth & development
  • Cerebral Cortex / metabolism
  • DNA-Binding Proteins / deficiency*
  • DNA-Binding Proteins / metabolism
  • Eye Proteins
  • Female
  • Fetus
  • Fluorescent Dyes
  • Growth Cones / metabolism*
  • Growth Cones / ultrastructure
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Internal Capsule / embryology
  • Internal Capsule / growth & development
  • Internal Capsule / metabolism
  • Mice
  • Mice, Knockout / embryology*
  • Mice, Knockout / growth & development
  • Mice, Knockout / metabolism
  • Mutation / genetics
  • Nervous System Malformations / genetics
  • Nervous System Malformations / metabolism
  • Nervous System Malformations / pathology
  • Neural Pathways / embryology*
  • Neural Pathways / growth & development
  • Neural Pathways / metabolism
  • PAX6 Transcription Factor
  • Paired Box Transcription Factors
  • Repressor Proteins
  • Thalamus / embryology*
  • Thalamus / growth & development
  • Thalamus / metabolism


  • 3,3'-dihexadecylindocarbocyanine
  • Carbocyanines
  • DNA-Binding Proteins
  • Eye Proteins
  • Fluorescent Dyes
  • Gbx2 protein, mouse
  • Homeodomain Proteins
  • PAX6 Transcription Factor
  • Paired Box Transcription Factors
  • Pax6 protein, mouse
  • Repressor Proteins
  • Tbr1 protein, mouse