title: TBR1 directly represses Fezf2 to control the laminar origin and development of the corticospinal tract.
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.
authors.affiliation: Department of Neurobiology, Kavli Institute of Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Wenqi
authors.initials: W
authors.lastname: Han
authors.forename: Kenneth Y
authors.initials: KY
authors.lastname: Kwan
authors.forename: Sungbo
authors.initials: S
authors.lastname: Shim
authors.forename: Mandy M S
authors.initials: MM
authors.lastname: Lam
authors.forename: Yurae
authors.initials: Y
authors.lastname: Shin
authors.forename: Xuming
authors.initials: X
authors.lastname: Xu
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhu
authors.forename: Mingfeng
authors.initials: M
authors.lastname: Li
authors.forename: Nenad
authors.initials: N
authors.lastname: Sestan
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology; D001483:Base Sequence; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D008156:Luciferases; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics; D011712:Pyramidal Tracts / Q000196:embryology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA; D020825:T-Box Domain Proteins
chemical_list: D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D020825:T-Box Domain Proteins; C492271:Tbr1 protein, mouse; C412364:Zfp312 protein, mouse; D008156:Luciferases