title: A network of genetic repression and derepression specifies projection fates in the developing neocortex.
abstract: Neurons within each layer in the mammalian cortex have stereotypic projections. Four genes-Fezf2, Ctip2, Tbr1, and Satb2-regulate these projection identities. These genes also interact with each other, and it is unclear how these interactions shape the final projection identity. Here we show, by generating double mutants of Fezf2, Ctip2, and Satb2, that cortical neurons deploy a complex genetic switch that uses mutual repression to produce subcortical or callosal projections. We discovered that Tbr1, EphA4, and Unc5H3 are critical downstream targets of Satb2 in callosal fate specification. This represents a unique role for Tbr1, implicated previously in specifying corticothalamic projections. We further show that Tbr1 expression is dually regulated by Satb2 and Ctip2 in layers 2-5. Finally, we show that Satb2 and Fezf2 regulate two disease-related genes, Auts2 (Autistic Susceptibility Gene2) and Bhlhb5 (mutated in Hereditary Spastic Paraplegia), providing a molecular handle to investigate circuit disorders in neurodevelopmental diseases.
authors.affiliation: Department of Biology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Karpagam
authors.initials: K
authors.lastname: Srinivasan
authors.forename: Dino P
authors.initials: DP
authors.lastname: Leone
authors.forename: Rosalie K
authors.initials: RK
authors.lastname: Bateson
authors.forename: Gergana
authors.initials: G
authors.lastname: Dobreva
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Kohwi
authors.forename: Terumi
authors.initials: T
authors.lastname: Kohwi-Shigematsu
authors.forename: Rudolf
authors.initials: R
authors.lastname: Grosschedl
authors.forename: Susan K
authors.initials: SK
authors.lastname: McConnell
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000201:enzymology; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D056426:Genetic Loci / Q000235:genetics; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D019579:Neocortex / Q000254:growth & development* / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D000075386:Netrin Receptors; D009474:Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding; D036122:Receptor, EphA4 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020825:T-Box Domain Proteins; D013788:Thalamus / Q000378:metabolism; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D000469:Alkaline Phosphatase; D051792:Basic Helix-Loop-Helix Proteins; D015816:Cell Adhesion Molecules, Neuronal; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D058851:GPI-Linked Proteins; D007527:Isoenzymes; D009419:Nerve Tissue Proteins; D000075386:Netrin Receptors; D009687:Nuclear Proteins; D036122:Receptor, EphA4; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; D020825:T-Box Domain Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C549397:Auts2 protein, mouse; C511143:Bcl11b protein, mouse; C488357:Bhlhe22 protein, mouse; C486733:Stab2 protein, mouse; C492271:Tbr1 protein, mouse; C105653:Unc5c protein, mouse; C412364:Zfp312 protein, mouse; C019839:alkaline phosphatase, placental