Gbx2 regulates thalamocortical axon guidance by modifying the LIM and Robo codes

Mallika Chatterjee, Kairong Li, Li Chen, Xu Maisano, Qiuxia Guo, Lin Gan, James Y.H. Li

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Combinatorial expression of transcription factors forms transcriptional codes to confer neuronal identities and connectivity. However, how these intrinsic factors orchestrate the spatiotemporal expression of guidance molecules to dictate the responsiveness of axons to guidance cues is less understood. Thalamocortical axons (TCAs) represent the major input to the neocortex and modulate cognitive functions, consciousness and alertness. TCAs travel a long distance and make multiple target choices en route to the cortex. The homeodomain transcription factor Gbx2 is essential for TCA development, as loss of Gbx2 abolishes TCAs in mice. Using a novel TCAspecific reporter, we have discovered that thalamic axons are mostly misrouted to the ventral midbrain and dorsal midline of the diencephalon in Gbx2-deficient mice. Furthermore, conditionally deleting Gbx2 at different embryonic stages has revealed a sustained role of Gbx2 in regulating TCA navigation and targeting. Using explant culture and mosaic analyses, we demonstrate that Gbx2 controls the intrinsic responsiveness of TCAs to guidance cues. The guidance defects of Gbx2-deficient TCAs are associated with abnormal expression of guidance receptors Robo1 and Robo2. Finally, we demonstrate that Gbx2 controls Robo expression by regulating LIM-domain transcription factors through three different mechanisms: Gbx2 and Lhx2 compete for binding to the Lmo3 promoter and exert opposing effects on its transcription; repressing Lmo3 by Gbx2 is essential for Lhx2 activity to induce Robo2; and Gbx2 represses Lhx9 transcription, which in turn induces Robo1. Our findings illustrate the transcriptional control of differential expression of Robo1 and Robo2, which may play an important role in establishing the topography of TCAs.

Original languageEnglish (US)
Pages (from-to)4633-4643
Number of pages11
JournalDevelopment (Cambridge)
Volume139
Issue number24
DOIs
StatePublished - Dec 15 2012
Externally publishedYes

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Keywords

  • Axon guidance
  • Lim domain proteins
  • Mouse
  • Robo
  • Thalamocortical projections
  • Transcription factor

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

Cite this

Chatterjee, M., Li, K., Chen, L., Maisano, X., Guo, Q., Gan, L., & Li, J. Y. H. (2012). Gbx2 regulates thalamocortical axon guidance by modifying the LIM and Robo codes. Development (Cambridge), 139(24), 4633-4643. https://doi.org/10.1242/dev.086991