TBR1 directly represses Fezf2 to control the laminar origin and development of the corticospinal tract

Proc Natl Acad Sci U S A. 2011 Feb 15;108(7):3041-6. doi: 10.1073/pnas.1016723108. Epub 2011 Feb 1.

Abstract

The corticospinal (CS) tract is involved in controlling discrete voluntary skilled movements in mammals. The CS tract arises exclusively from layer (L) 5 projection neurons of the cerebral cortex, and its formation requires L5 activity of Fezf2 (Fezl, Zfp312). How this L5-specific pattern of Fezf2 expression and CS axonal connectivity is established with such remarkable fidelity had remained elusive. Here we show that the transcription factor TBR1 directly binds the Fezf2 locus and represses its activity in L6 corticothalamic projection neurons to restrict the origin of the CS tract to L5. In Tbr1 null mutants, CS axons ectopically originate from L6 neurons in a Fezf2-dependent manner. Consistently, misexpression of Tbr1 in L5 CS neurons suppresses Fezf2 expression and effectively abolishes the CS tract. Taken together, our findings show that TBR1 is a direct transcriptional repressor of Fezf2 and a negative regulator of CS tract formation that restricts the laminar origin of CS axons specifically to L5.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Axons / pathology
  • Base Sequence
  • Chromatin Immunoprecipitation
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation, Developmental / physiology*
  • Luciferases
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Plasmids / genetics
  • Pyramidal Tracts / embryology*
  • Pyramidal Tracts / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Analysis, DNA
  • Sequence Analysis, RNA
  • T-Box Domain Proteins

Substances

  • DNA-Binding Proteins
  • Nerve Tissue Proteins
  • T-Box Domain Proteins
  • Tbr1 protein, mouse
  • Zfp312 protein, mouse
  • Luciferases